Management of febrile neutropenia in the United Kingdom: time for a national trial?

Recent advances in febrile neutropenia (FN) have highlighted the value of risk stratification and the evolving role of oral antibiotics with early hospital discharge in low-risk patients. The aim of this study was to survey whether these advances have been translated into routine clinical practice in the UK. Questionnaires were sent to cancer clinicians across the UK to determine clinicians' routine management of FN, including use of risk stratification, antibiotic regimen and criteria for hospital discharge. In all, 128 clinicians responded, representing 50 cancer departments (83%). Only 38% of respondents stratify patients according to risk and with substantial variation in the criteria defining ‘low-risk'. Furthermore, only 22% of clinicians use oral antibiotics as first-line treatment in any patients with FN, but this was significantly greater among clinicians who do compared to those who do not stratify patients by risk, 51 vs 4% (P<0.0001). These findings suggest a slow and/or cautious introduction of newer strategies for the management of low-risk FN in the UK. However, 84% of respondents confirmed their willingness to participate in a trial of oral antibiotics combined with early discharge in low-risk FN

Phenotyping clonal populations of glioma stem cell reveals a high degree of plasticity in response to changes of microenvironment

The phenotype of glioma-initiating cells (GIC) is modulated by cell-intrinsic and cell-extrinsic factors. Phenotypic heterogeneity and plasticity of GIC is an important limitation to therapeutic approaches targeting cancer stem cells. Plasticity also presents a challenge to the identification, isolation, and propagation of purified cancer stem cells. Here we use a barcode labelling approach of GIC to generate clonal populations over a number of passages, in combination with phenotyping using the established stem cell markers CD133, CD15, CD44, and A2B5. Using two cell lines derived from isocitrate dehydrogenase (IDH)-wildtype glioblastoma, we identify a remarkable heterogeneity of the phenotypes between the cell lines. During passaging, clonal expansion manifests as the emergence of a limited number of barcoded clones and a decrease in the overall number of clones. Dual-labelled GIC are capable of forming traceable clonal populations which emerge after as few as two passages from mixed cultures and through analyses of similarity of relative proportions of 16 surface markers we were able to pinpoint the fate of such populations. By generating tumour organoids we observed a remarkable persistence of dominant clones but also a significant plasticity of stemness marker expression. Our study presents an experimental approach to simultaneously barcode and phenotype glioma-initiating cells to assess their functional properties, for example to screen newly established GIC for tumour-specific therapeutic vulnerabilities

The efficacy of silver diamine fluoride in arresting caries in children

Data sourcesPubMed, Scopus, Web of Science, the Latin American and Caribbean Health Sciences Literature database (LILACS), the Brazilian Library in Dentistry (BBO), Cochrane Library and grey literature.Study selectionTwo reviewers selected randomised clinical trials (RCTs) that compared the efficacy of SDF application with other active treatments or placebo in arresting carious lesions.Data extraction and synthesisThree authors extracted data using customised extraction forms, and risk of bias was assessed by two independent reviewers. Meta-analyses were performed on studies classified at 'low' or 'unclear' risk of bias, where similar outcomes were recorded in primary teeth, and that compared SDF to active treatments.ResultsEleven studies were included; five studies were at 'low', two at 'unclear' and four studies at 'high' risk of bias. Eight were conducted with primary teeth, two with permanent first molars and one conducted on both. Six studies used 38% SDF, two 30% SDF, one 12% SDF, one compared 38% SDF to 12% SDF and one used Nano Silver Fluoride (NSF).ConclusionsSDF is more effective than active treatments or placebo for carious lesion arrest in primary teeth. The body of evidence was of high quality for primary teeth. However, there was not enough high quality evidence to draw conclusions about carious lesion arrest in first permanent molars

Elastin is Localised to the Interfascicular Matrix of Energy Storing Tendons and Becomes Increasingly Disorganised With Ageing

Tendon is composed of fascicles bound together by the interfascicular matrix (IFM). Energy storing tendons are more elastic and extensible than positional tendons; behaviour provided by specialisation of the IFM to enable repeated interfascicular sliding and recoil. With ageing, the IFM becomes stiffer and less fatigue resistant, potentially explaining why older tendons become more injury-prone. Recent data indicates enrichment of elastin within the IFM, but this has yet to be quantified. We hypothesised that elastin is more prevalent in energy storing than positional tendons, and is mainly localised to the IFM. Further, we hypothesised that elastin becomes disorganised and fragmented, and decreases in amount with ageing, especially in energy storing tendons. Biochemical analyses and immunohistochemical techniques were used to determine elastin content and organisation, in young and old equine energy storing and positional tendons. Supporting the hypothesis, elastin localises to the IFM of energy storing tendons, reducing in quantity and becoming more disorganised with ageing. These changes may contribute to the increased injury risk in aged energy storing tendons. Full understanding of the processes leading to loss of elastin and its disorganisation with ageing may aid in the development of treatments to prevent age related tendinopathy

Survey of the quality of experimental design, statistical analysis and reporting of research using animals

For scientific, ethical and economic reasons, experiments involving animals should be appropriately designed, correctly analysed and transparently reported. This increases the scientific validity of the results, and maximises the knowledge gained from each experiment. A minimum amount of relevant information must be included in scientific publications to ensure that the methods and results of a study can be reviewed, analysed and repeated. Omitting essential information can raise scientific and ethical concerns. We report the findings of a systematic survey of reporting, experimental design and statistical analysis in published biomedical research using laboratory animals. Medline and EMBASE were searched for studies reporting research on live rats, mice and non-human primates carried out in UK and US publicly funded research establishments. Detailed information was collected from 271 publications, about the objective or hypothesis of the study, the number, sex, age and/or weight of animals used, and experimental and statistical methods. Only 59% of the studies stated the hypothesis or objective of the study and the number and characteristics of the animals used. Appropriate and efficient experimental design is a critical component of high-quality science. Most of the papers surveyed did not use randomisation (87%) or blinding (86%), to reduce bias in animal selection and outcome assessment. Only 70% of the publications that used statistical methods described their methods and presented the results with a measure of error or variability. This survey has identified a number of issues that need to be addressed in order to improve experimental design and reporting in publications describing research using animals. Scientific publication is a powerful and important source of information; the authors of scientific publications therefore have a responsibility to describe their methods and results comprehensively, accurately and transparently, and peer reviewers and journal editors share the responsibility to ensure that published studies fulfil these criteria

"It's really no more difficult than putting on fluoride varnish":a qualitative exploration of dental professionals' views of silver diamine fluoride for the management of carious lesions in children

Background Despite evidence that Silver Diamine Fluoride (SDF) can be effective in managing carious lesions in primary teeth, the use of SDF in the UK remains limited. This study explored dental professionals’ views and experiences of using SDF for managing carious lesions in children. In addition, it explored what they perceived to be the advantages, disadvantages, barriers and enablers to the use of SDF in practice. Methods Fifteen semi-structured face-to-face or over-the-phone interviews were conducted with 14 dental professionals from NHS Tayside and NHS Grampian in Scotland. Interviews were transcribed verbatim, coded and analysed using a thematic approach. Results Thirteen of 14 dental professionals interviewed were familiar with, or had some existing knowledge of, SDF. Four had used it to treat patients. The majority of participants thought that the main advantage of SDF was that it required minimal patient cooperation. SDF was also perceived as a simple, pain-free and non-invasive treatment approach that could help acclimatise children to the dental environment. However, SDF-induced black staining of arrested carious lesions was most commonly reported as the main disadvantage and greatest barrier to using it in practice. Participants believed that this discolouration would concern some parents who may fear that the black appearance may instigate bullying at school and that others may judge parents as neglecting their child’s oral health. Participants thought that education of clinicians about SDF use and information sheets for parents would enhance the uptake of SDF in dental practice. Participants believed that younger children might not be as bothered by the discolouration as older ones and they anticipated greater acceptance of SDF for posterior primary teeth by both parents and children. Conclusion Dental professionals were aware that SDF can be used for arresting carious lesions. They pointed out that the staining effect of carious lesions is a major disadvantage that could be a barrier for many parents. Participants considered the application process to be simple and non-invasive and requires a minimum level of child cooperation. Participants appreciated the potential of SDF in paediatric dentistry and suggested actions that could help overcome the barriers they highlighted

A multi-species cluster of GES-5 carbapenemase producing Enterobacterales linked by a geographically disseminated plasmid

BACKGROUND: Early and accurate treatment of infections due to carbapenem-resistant organisms is facilitated by rapid diagnostics but rare resistance mechanisms can compromise detection. One year after a GES-5 carbapenemase-positive Klebsiella oxytoca infection was identified by whole genome sequencing (WGS) (later found to be part of a cluster of three cases), a cluster of 11 patients with GES-5-positive K. oxytoca was identified over 18 weeks in the same hospital. METHODS: Bacteria were identified by MALDI-TOF, antimicrobial susceptibility testing followed EUCAST guidelines. Ertapenem-resistant isolates were referred to Public Health England for characterization using PCR detection of GES, pulse-field gel electrophoresis (PFGE) and WGS for the second cluster. RESULTS: The identification of the first GES-5 K. oxytoca isolate was delayed, being identified on WGS. A GES-gene PCR informed the occurrence of the second cluster in real-time. In contrast to PFGE, WGS phylogenetic analysis refuted an epidemiological link between the two clusters; it also suggested a cascade of patient-to-patient transmission in the later cluster. A novel GES-5-encoding plasmid was present in K. oxytoca,E. coli and E. cloacae isolates from unlinked patients within the same hospital group and in human and wastewater isolates from three hospitals elsewhere in the UK. CONCLUSIONS: Genomic sequencing revolutionized the epidemiological understanding of the clusters, it also underlined the risk of covert plasmid propagation in healthcare settings and revealed the national distribution of the resistance-encoding plasmid. Sequencing results also informed and led to the ongoing use of enhanced diagnostic tests for detecting carbapenemases locally and nationally

Estrogen-dependent dynamic profile of eNOS-DNA associations in prostate cancer

In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa

Grip strength measurements at two different wrist extension positions in chronic lateral epicondylitis-comparison of involved vs. uninvolved side in athletes and non athletes: a case-control study

Abstract Background Lateral epicondylitis is a common sports injury of the elbow caused due to altered muscle activation during repetitive wrist extension in many athletic and non-athletic endeavours. The amount of muscle activity and timing of contraction eventually is directly dependent upon joint position during the activity. The purpose of our study was to compare the grip strength in athletes with lateral epicondylalgia in two different wrist extension positions and compare them between involved and uninvolved sides of athletes and non-athletes. Methods An assessor-blinded case-control study of eight athletes and twenty-two non-athletes was done. The grip strength was measured using JAMAR® hand dynamometer in kilograms-force at 15 degrees (slightly extended) and 35 degrees (moderately extended) wrist extension positions (maintained by wrist splints) on both involved and uninvolved sides of athletes and non-athletes with unilateral lateral epicondylitis of atleast 3 months duration. Their pain was to be elicited with local tenderness and two of three tests being positive- Cozen's, Mill's manoeuvre, resisted middle finger extension tests. For comparisons of grip strength, Wilcoxon signed rank test was used for within-group comparison (between 15 and 35 degrees wrist extension positions) and Mann-Whitney U test was used for between-group (athletes vs. non-athletes) comparisons at 95% confidence interval and were done using SPSS 11.5 for Windows. Results Statistically significant greater grip strength was found in 15 degrees (27.75 ± 4.2 kgms in athletes; 16.45 ± 4.2 kgms in non-athletes) wrist extension than at 35 degrees (25.25 ± 3.53 kgm in athletes and 14.18 ± 3.53 kgm in non-athletes). The athletes had greater grip strength than non-athletes in each of test positions (11.3 kgm at 15 degrees and 11.07 kgm at 35 degrees) measured. There was also a significant difference between involved and uninvolved sides' grip strength at both wrist positions (4.44 ± .95 kgm at 15 degrees and 4.44 ± .86 kgm in 35 degrees) which was significant (p Conclusion The grip strength was greater in 15 degrees wrist extension position and this position could then be used in athletes with lateral epicondylalgia for grip strength assessment and designing wrist splint in this population.</p