Balancing sub- and supra-salt strain in salt-influenced rifts: Implications for extension estimates

The structural style of salt-influenced rifts may differ from those formed in predominantly brittle crust. Salt can decouple sub- and supra-salt strain, causing sub-salt faults to be geometrically decoupled from, but kinematically coupled to and responsible for, supra-salt forced folding. Salt-influenced rifts thus contain more folds than their brittle counterparts, an observation often ignored in extension estimates. Fundamental to determining whether sub- and supra-salt structures are kinematically coherent, and the relative contributions of thin- (i.e. gravity-driven) and thick-skinned (i.e. whole-plate stretching) deformation to accommodating rift-related strain, is our ability to measure extension at both structural levels. We here use published physical models of salt-influenced extension to show that line-length estimates yield more accurate values of sub- and supra-salt extension compared to fault-heave, before applying these methods to seismic data from the Halten Terrace, offshore Norway. We show that, given the abundance of ductile deformation in salt-influenced rifts, significant amounts of extension may be ignored, leading to the erroneous interpretations of thin-skinned, gravity-gliding. If a system is kinematically coherent, supra-salt structures can help predict the occurrence and kinematics of sub-salt faults that may be poorly imaged and otherwise poorly constrained

Long-term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy Screening randomised controlled trial

National Institute for Health Research Efficacy and Mechanism Evaluation

An investigation of scale effects in family substance abuse treatment programs

This short report investigates scale effects in family substance abuse treatment programs. In Massachusetts, the family substance abuse treatment programs were much more costly than other adult residential treatment models. State officials were concerned that the "scale" or size of these programs (averaging just eight families) was too small to be economical. Although the sample size (just nine programs) was too small to permit reliable inference, the data clearly signalled the importance of "scale effects" in these family substance abuse treatment programs. To further investigate scale effects in family substance abuse treatment programs, data from the Center for Substance Abuse Treatment's (CSAT's) Residential Women and Children and Pregnant and Postpartum Women (RWC-PPW) Demonstration were re-analyzed, focusing on the relationship between cost per family-day and the estimated average family census. This analysis indicates strong economies of scale up until an average family census of about 14, and less apparent scale effects beyond that point. In consideration of these and other study findings, a multidisciplinary interagency team redesigned the Massachusetts' family treatment program model. The new programs are larger than the former family treatment programs, with each new program having capacity to treat 11 to 15 families depending on family makeup

Assessing constancy of substitution rates in viruses over evolutionary time

<p>Abstract</p> <p>Background</p> <p>Phylogenetic analyses reveal probable patterns of divergence of present day organisms from common ancestors. The points of divergence of lineages can be dated if a corresponding historical or fossil record exists. For many species, in particular viruses, such records are rare. Recently, Bayesian phylogenetic analysis using sequences from closely related organisms isolated at different times have been used to calibrate divergences. Phylogenetic analyses depend on the assumption that the average substitution rates that can be calculated from the data apply throughout the course of evolution. </p> <p>Results</p> <p>The present study tests this crucial assumption by charting the kinds of substitutions observed between pairs of sequences with different levels of total substitutions. Datasets of aligned sequences, both viral and non-viral, were assembled. For each pair of sequences in an aligned set, the distribution of nucleotide interchanges and the total number of changes were calculated. Data were binned according to total numbers of changes and plotted. The accumulation of the six possible interchange types in retroelements as a function of distance followed closely the expected hyperbolic relationship. For other datasets, however, significant deviations from this relationship were noted. A rapid initial accumulation of transition interchanges was frequent among the datasets and anomalous changes occurred at specific divergence levels. </p> <p>Conclusions</p> <p>The accumulation profiles suggested that substantial changes in frequencies of types of substitutions occur over the course of evolution and that such changes should be considered in evaluating and dating viral phylogenies.</p

Including a general practice endorsement letter with the testing kit in the Bowel Cancer Screening Programme: Results of a cluster randomised trial

Objectives: To evaluate the effect of general practitioner endorsement accompanying the screening kit rather than with the invitation letter on participation in the NHS Bowel Cancer Screening Programme and on the socioeconomic gradient in participation in the Programme. Methods: The NHS Bowel Cancer Screening Programme in England is delivered via five regional hubs. In early 2016, we carried out a cluster-randomised trial, with hub-day of invitation as the randomisation unit. We randomised 150 hub-days of invitation to the intervention group, GP endorsement on the letter accompanying the guaiac faecal occult blood testing kit (75 hub-days, 197,366 individuals) or control, usual letter (75 hub-days, 197,476 individuals). The endpoint was participation, defined as return of a valid kit within 18 weeks of initial invitation. Because of the cluster randomisation, data were analysed by a hierarchical logistic regression, allowing a random effect for date of invitation. Socioeconomic status was represented by the index of multiple deprivation. Results: Participation was 59.4% in the intervention group and 58.7% in the control group, a significant difference (p = 0.04). There was no heterogeneity of the effect of intervention by index of multiple deprivation. We found that there was some confounding between date and screening episode order (first or subsequent screen). This in turn may have induced confounding with age and slightly diluted the result. Conclusions: General practitioner endorsement induces a modest increase in participation in bowel cancer screening, but does not affect the socioeconomic gradient. When considering cluster randomisation as a research method, careful scrutiny of potential confounding is indicated in advance if possible and in analysis otherwise

Confirmation of low genetic diversity and multiple breeding females in a social group of Eurasian badgers from microsatellite and field data

The Eurasian badger ( Meles meles ) is a facultatively social carnivore that shows only rudimentary co-operative behaviour and a poorly defined social hierarchy. Behavioural evidence and limited genetic data have suggested that more than one female may breed in a social group. We combine pregnancy detection by ultrasound and microsatellite locus scores from a well-studied badger population from Wytham Woods, Oxfordshire, UK, to demonstrate that multiple females reproduce within a social group. We found that at least three of seven potential mothers reproduced in a group that contained 11 reproductive age females and nine offspring. Twelve primers showed variability across the species range and only five of these were variable in Wytham. The microsatellites showed a reduced repeat number, a significantly higher number of nonperfect repeats, and moderate heterozygosity levels in Wytham. The high frequency of imperfect repeats and demographic phenomena might be responsible for the reduced levels of variability observed in the badger

Cardiosphere-derived cells suppress allogeneic lymphocytes by production of PGE2 acting via the EP4 receptor

derived cells (CDCs) are a cardiac progenitor cell population, which have been shown to possess cardiac regenerative properties and can improve heart function in a variety of cardiac diseases. Studies in large animal models have predominantly focussed on using autologous cells for safety, however allogeneic cell banks would allow for a practical, cost-effective and efficient use in a clinical setting. The aim of this work was to determine the immunomodulatory status of these cells using CDCs and lymphocytes from 5 dogs. CDCs expressed MHC I but not MHC II molecules and in mixed lymphocyte reactions demonstrated a lack of lymphocyte proliferation in response to MHC-mismatched CDCs. Furthermore, MHC-mismatched CDCs suppressed lymphocyte proliferation and activation in response to Concanavalin A. Transwell experiments demonstrated that this was predominantly due to direct cell-cell contact in addition to soluble mediators whereby CDCs produced high levels of PGE2 under inflammatory conditions. This led to down-regulation of CD25 expression on lymphocytes via the EP4 receptor. Blocking prostaglandin synthesis restored both, proliferation and activation (measured via CD25 expression) of stimulated lymphocytes. We demonstrated for the first time in a large animal model that CDCs inhibit proliferation in allo-reactive lymphocytes and have potent immunosuppressive activity mediated via PGE2

Post-polypectomy surveillance interval and advanced neoplasia detection rates: a multicenter, retrospective cohort study

Background Longer post-polypectomy surveillance intervals are associated with increased colorectal neoplasia detection at surveillance in some studies. We investigated this association to inform optimal surveillance intervals. Methods Patients who underwent colonoscopy and post-polypectomy surveillance at 17 UK hospitals were classified as low/high risk by baseline findings. We compared detection rates of advanced adenomas (≥ 10 mm, tubulovillous/villous, high grade dysplasia), high risk findings (HRFs: ≥ 2 serrated polyps/[adenomas] of which ≥ 1 is ≥ 10 mm or has [high grade] dysplasia; ≥ 5 serrated polyps/adenomas; or ≥ 1 nonpedunculated polyp ≥ 20 mm), or colorectal cancer (CRC) at surveillance colonoscopy by surveillance interval (< 18 months, 2, 3, 4, 5, 6 years). Risk ratios (RRs) were estimated using multivariable regression. Results Of 11 214 patients, 7216 (64 %) were low risk and 3998 (36 %) were high risk. Among low risk patients, advanced adenoma, HRF, and CRC detection rates at first surveillance were 7.8 %, 3.7 %, and 1.1 %, respectively. Advanced adenoma detection increased with increasing surveillance interval, reaching 9.8 % with a 6-year interval (P trend < 0.001). Among high risk patients, advanced adenoma, HRF, and CRC detection rates at first surveillance were 15.3 %, 10.0 %, and 1.5 %, respectively. Advanced adenoma and CRC detection rates (P trends < 0.001) increased with increasing surveillance interval; RRs (95 % confidence intervals) for CRC were 1.54 (0.68–3.48), 4.44 (1.95–10.08), and 5.80 (2.51–13.40) with 3-, 4-, and 5-year intervals, respectively, versus an interval of < 18 months. Conclusions Metachronous neoplasia was uncommon among low risk patients, even with long surveillance intervals, supporting recommendations for no surveillance in these patients. For high risk patients, a 3-year surveillance interval would ensure timely CRC detection

A systematic variation of the stellar initial mass function in early-type galaxies

Much of our knowledge of galaxies comes from analysing the radiation emitted by their stars. It depends on the stellar initial mass function (IMF) describing the distribution of stellar masses when the population formed. Consequently knowledge of the IMF is critical to virtually every aspect of galaxy evolution. More than half a century after the first IMF determination, no consensus has emerged on whether it is universal in different galaxies. Previous studies indicated that the IMF and the dark matter fraction in galaxy centres cannot be both universal, but they could not break the degeneracy between the two effects. Only recently indications were found that massive elliptical galaxies may not have the same IMF as our Milky Way. Here we report unambiguous evidence for a strong systematic variation of the IMF in early-type galaxies as a function of their stellar mass-to-light ratio, producing differences up to a factor of three in mass. This was inferred from detailed dynamical models of the two-dimensional stellar kinematics for the large Atlas3D representative sample of nearby early-type galaxies spanning two orders of magnitude in stellar mass. Our finding indicates that the IMF depends intimately on a galaxy's formation history.Comment: 4 pages, 2 figures, LaTeX. Accepted for publication as a Nature Letter. More information about our Atlas3D project is available at http://purl.org/atlas3

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years