Hydrodynamic simulations of shell convection in stellar cores

Shell convection driven by nuclear burning in a stellar core is a common hydrodynamic event in the evolution of many types of stars. We encounter and simulate this convection (i) in the helium core of a low-mass red giant during core helium flash leading to a dredge-down of protons across an entropy barrier, (ii) in a carbon-oxygen core of an intermediate-mass star during core carbon flash, and (iii) in the oxygen and carbon burning shell above the silicon-sulfur rich core of a massive star prior to supernova explosion. Our results, which were obtained with the hydrodynamics code HERAKLES, suggest that both entropy gradients and entropy barriers are less important for stellar structure than commonly assumed. Our simulations further reveal a new dynamic mixing process operating below the base of shell convection zones.Comment: 8 pages, 3 figures .. submitted to a proceedings of conference about "Red Giants as Probes of the Structure and Evolution of the Milky Way" which has taken place between 15-17 November 2010 in Rom

Solar cycle variation in solar f-mode frequencies and radius

Using data from the Global Oscillation Network Group (GONG) covering the period from 1995 to 1998, we study the change with solar activity in solar f-mode frequencies. The results are compared with similar changes detected from the Michelson Doppler Imager (MDI) data. We find variations in f-mode frequencies which are correlated with solar activity indices. If these changes are due to variation in solar radius then the implications are that the solar radius decreases by about 5 km from minimum to maximum activity.Comment: To appear in Solar Physic

Epithelial cell shedding and barrier function: a matter of life and death at the small intestinal villus tip

The intestinal epithelium is a critical component of the gut barrier. Composed of a single layer of intestinal epithelial cells (IECs) held together by tight junctions, this delicate structure prevents the transfer of harmful microorganisms, antigens, and toxins from the gut lumen into the circulation. The equilibrium between the rate of apoptosis and shedding of senescent epithelial cells at the villus tip, and the generation of new cells in the crypt, is key to maintaining tissue homeostasis. However, in both localized and systemic inflammation, this balance may be disturbed as a result of pathological IEC shedding. Shedding of IECs from the epithelial monolayer may cause transient gaps or microerosions in the epithelial barrier, resulting in increased intestinal permeability. Although pathological IEC shedding has been observed in mouse models of inflammation and human intestinal conditions such as inflammatory bowel disease, understanding of the underlying mechanisms remains limited. This process may also be an important contributor to systemic and intestinal inflammatory diseases and gut barrier dysfunction in domestic animal species. This review aims to summarize current knowledge about intestinal epithelial cell shedding, its significance in gut barrier dysfunction and host-microbial interactions, and where research in this field is directed

A recent whole-genome duplication divides populations of a globally-distributed microsporidian

This is the final version of the article. Available from Oxford University Press via the DOI in this record.The Microsporidia are a major group of intracellular fungi and important parasites of animals including insects, fish, and immunocompromised humans. Microsporidian genomes have undergone extreme reductive evolution but there are major differences in genome size and structure within the group: some are prokaryote-like in size and organisation (<3 Mb of gene-dense sequence) whilst others have more typically eukaryotic genome architectures. To gain fine-scale, population-level insight into the evolutionary dynamics of these tiny eukaryotic genomes, we performed the broadest microsporidian population genomic study to date, sequencing geographically isolated strains of Spraguea, a marine microsporidian infecting goosefish worldwide. Our analysis revealed that population structure across the Atlantic Ocean is associated with a conserved difference in ploidy, with American and Canadian isolates sharing an ancestral whole genome duplication that was followed by widespread pseudogenisation and sorting-out of paralogue pairs. Whilst past analyses have suggested de novo gene formation of microsporidian-specific genes, we found evidence for the origin of new genes from noncoding sequence since the divergence of these populations. Some of these genes experience selective constraint, suggesting the evolution of new functions and local host adaptation. Combining our data with published microsporidian genomes, we show that nucleotide composition across the phylum is shaped by a mutational bias favouring A and T nucleotides, which is opposed by an evolutionary force favouring an increase in genomic GC content. This work reveals ongoing dramatic reorganisation of genome structure and the evolution of new gene functions in modern microsporidians despite extensive genomic streamlining in their common ancestor.The authors would like to thank John Brookfield and David Studholme for helpful discussions. This work was supported by a Marie Curie Intra-European postdoctoral fellowship (T.A.W.) and the European Research Council Advanced Investigator Programme and the Wellcome Trust (grant numbers ERC- 2010- AdG-268701 045404 to T.M.E.) It is also supported by a Royal Society University Research Fellowship (B.A.P.W.)

Low-dose computed tomography for lung cancer screening in high risk populations: a systematic review and economic evaluation

This is the final version. Available from NIHR Journals Library via the DOI in this record.The dataset associated with this article is located in ORE at: https://doi.org/10.24378/exe.564Background Diagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early. Objectives To estimate the effectiveness and cost-effectiveness of LDCT lung cancer screening in high risk populations. Methods Clinical effectiveness A systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programme (such as chest X-ray (CXR)) was conducted. Bibliographic sources included MEDLINE, Embase, Web of Science and the Cochrane Library. Meta-analyses, including network meta-analyses, were performed. Cost-effectiveness An independent economic model employing discrete event simulation and using a natural history model calibrated to results from a large RCT was developed. There were twelve different population eligibility criteria and four intervention frequencies (single screen, triple screen, annual screening and biennial screening) and a no screening control arm. Results Clinical effectiveness Twelve RCTs were included, four of which currently contribute evidence on mortality. Meta-analysis of these demonstrated that LDCT with up to 9.80 years of follow-up was associated with a non-statistically significant decrease in lung cancer mortality (pooled RR 0.94, 95% CI 0.74 to 1.19). The findings also showed that LDCT screening demonstrated a non-statistically significant increasein all-cause mortality. Given the considerable heterogeneity detected between studies for both outcomes, the results should be treated with caution. Network meta-analysis including six RCTs was performed to assess the relative effectiveness of LDCT, CXR and usual care. The results showed that LDCT was ranked as the best screening strategy in terms of lung cancer mortality reduction. CXR had a 99.7% probability of being the worst intervention with usual care intermediate. Cost-effectiveness Screening programmes are predicted to be more effective than no screening, reduce lung cancer mortality and result in more lung cancer diagnoses. Screening programmes also increase costs. Screening for lung cancer is unlikely to be cost-effective at a threshold of £20,000/QALY, but may be cost-effective at a threshold of £30,000/QALY. The incremental cost-effectiveness ratio for a single screen in smokers aged 60–75 years with at least a 3% risk of lung cancer is £28,169 per QALY. Sensitivity and scenario analyses were conducted. Screening was only cost-effective at a threshold of £20,000/QALY in a minority of analyses. Limitations Clinical effectiveness The largest of the included RCTs compared LDCT with CXR screening rather than no screening. Cost-effectiveness A representative cost to the NHS of lung cancer has not been recently estimated according to key variables such as stage at diagnosis. Certain costs associated with running a screening programme have not been included. Conclusions LDCT screening may be clinically effective in reducing lung cancer mortality but there is considerable uncertainty. There is evidence that a single round of screening could be considered cost-effective at conventional thresholds, but there is significant uncertainty about the effect on costs and the magnitude of benefits. Future work Effectiveness and cost-effectiveness estimates should be updated with the anticipated results from several ongoing RCTs (particularly NELSON).This report was commissioned by the NIHR Health Technology Assessment Programme as project number 14/151/0

Identification of Post-Transcriptional Modulators of Breast Cancer Transcription Factor Activity Using MINDy

We have recently identified transcription factors (TFs) that are key drivers of breast cancer risk. To better understand the pathways or sub-networks in which these TFs mediate their function we sought to identify upstream modulators of their activity. We applied the MINDy (Modulator Inference by Network Dynamics) algorithm to four TFs (ESR1, FOXA1, GATA3 and SPDEF) that are key drivers of estrogen receptor-positive (ER+) breast cancer risk, as well as cancer progression. Our computational analysis identified over 500 potential modulators. We assayed 189 of these and identified 55 genes with functional characteristics that were consistent with a role as TF modulators. In the future, the identified modulators may be tested as potential therapeutic targets, able to alter the activity of TFs that are critical in the development of breast cancer

Non-invasive MRI biomarkers for the early assessment of iron overload in a humanized mouse model of β-thalassemia

β-thalassemia (βT) is a genetic blood disorder causing profound and life threatening anemia. Current clinical management of βT is a lifelong dependence on regular blood transfusions, a consequence of which is systemic iron overload leading to acute heart failure. Recent developments in gene and chelation therapy give hope of better prognosis for patients, but successful translation to clinical practice is hindered by the lack of thorough preclinical testing using representative animal models and clinically relevant quantitative biomarkers. Here we demonstrate a quantitative and non-invasive preclinical Magnetic Resonance Imaging (MRI) platform for the assessment of βT in the γβ(0)/γβ(A) humanized mouse model of βT. Changes in the quantitative MRI relaxation times as well as severe splenomegaly were observed in the heart, liver and spleen in βT. These data showed high sensitivity to iron overload and a strong relationship between quantitative MRI relaxation times and hepatic iron content. Importantly these changes preceded the onset of iron overload cardiomyopathy, providing an early biomarker of disease progression. This work demonstrates that multiparametric MRI is a powerful tool for the assessment of preclinical βT, providing sensitive and quantitative monitoring of tissue iron sequestration and cardiac dysfunction- parameters essential for the preclinical development of new therapeutics

A randomised controlled trial to assess the effectiveness of a single session of nurse administered massage for short term relief of chronic non-malignant pain

Background: Massage is increasingly used to manage chronic pain but its benefit has not been clearly established. The aim of the study is to determine the effectiveness of a single session of nurse-administered massage for the short term relief of chronic non-malignant pain and anxiety. Methods: A randomised controlled trial design was used, in which the patients were assigned to a massage or control group. The massage group received a 15 minute manual massage and the control group a 15 minute visit to talk about their pain. Adult patients attending a pain relief unit with a diagnosis of chronic pain whose pain was described as moderate or severe were eligible for the study. An observer blind to the patients' treatment group carried out assessments immediately before (baseline), after treatment and 1, 2, 3 and 4 hours later. Pain was assessed using 100 mm visual analogue scale and the McGill Pain Questionnaire. Pain Relief was assessed using a five point verbal rating scale. Anxiety was assessed with the Spielberger short form State-Trait Anxiety Inventory. Results: 101 patients were randomised and evaluated, 50 in the massage and 51 in the control group. There were no statistically significant differences between the groups at baseline interview. Patients in the massage but not the control group had significantly less pain compared to baseline immediately after and one hour post treatment. 95% confidence interval for the difference in mean pain reduction at one hour post treatment between the massage and control groups is 5.47 mm to 24.70 mm. Patients in the massage but not the control group had a statistically significant reduction in anxiety compared to baseline immediately after and at 1 hour post treatment. Conclusion: Massage is effective in the short term for chronic pain of moderate to severe intensity

Designing theoretically-informed implementation interventions

Clinical and health services research is continually producing new findings that may contribute to effective and efficient patient care. However, the transfer of research findings into practice is unpredictable and can be a slow and haphazard process. Ideally, the choice of implementation strategies would be based upon evidence from randomised controlled trials or systematic reviews of a given implementation strategy. Unfortunately, reviews of implementation strategies consistently report effectiveness some, but not all of the time; possible causes of this variation are seldom reported or measured by the investigators in the original studies. Thus, any attempts to extrapolate from study settings to the real world are hampered by a lack of understanding of the effects of key elements of individuals, interventions, and the settings in which they were trialled. The explicit use of theory offers a way of addressing these issues and has a number of advantages, such as providing: a generalisable framework within which to represent the dimensions that implementation studies address, a process by which to inform the development and delivery of interventions, a guide when evaluating, and a way to allow for an exploration of potential causal mechanisms. However, the use of theory in designing implementation interventions is methodologically challenging for a number of reasons, including choosing between theories and faithfully translating theoretical constructs into interventions. The explicit use of theory offers potential advantages in terms of facilitating a better understanding of the generalisability and replicability of implementation interventions. However, this is a relatively unexplored methodological area