Breast cancer worry in higher-risk women offered preventive therapy: a UK multicentre prospective study

PURPOSE: Women's worry about developing breast cancer may influence their decision to use preventive therapy. However, the direction of this relationship has been questioned. We prospectively investigated the relationship between breast cancer worry and uptake of preventive therapy. The socio-demographic and clinical factors associated with high breast cancer worry were also investigated. METHODS: Women at increased risk of developing breast cancer were recruited from clinics across England (n = 408). Participants completed a survey on their breast cancer worry, socio-demographic and clinical factors. Uptake of tamoxifen was recorded at 3 months (n = 258 women, 63.2%). Both primary and sensitivity analyses were conducted using different classifications of low, medium and high worry. RESULTS: 39.5% of respondents reported medium breast cancer worry at baseline and 21.2% reported high worry. Ethnic minority women were more likely to report high worry than white women (OR = 3.02, 95%CI 1.02, 8.91, p = 0.046). Women educated below degree level were more likely to report high worry than those with higher education (OR = 2.29, 95%CI 1.28, 4.09, p = 0.005). No statistically significant association was observed between worry and uptake. In the primary analysis, fewer respondents with medium worry at baseline initiated tamoxifen (low worry = 15.5%, medium = 13.5%, high = 15.7%). In the sensitivity analysis, participants with medium worry reported the highest uptake of tamoxifen (19.7%). CONCLUSIONS: No association was observed between worry and uptake, although the relationship was affected by the categorisation of worry. Standardised reporting of the classification of worry is warranted to allow transparent comparisons across cohorts

The effects of ram-pressure stripping on the internal kinematics of simulated spiral galaxies

We investigate the influence of ram-pressure stripping on the internal gas kinematics of simulated spiral galaxies. Additional emphasis is put on the question of how the resulting distortions of the gaseous disc are visible in the rotation curve and/or the full 2D velocity field of galaxies at different redshifts. A Milky-Way type disc galaxy is modelled in combined N-body/hydrodynamic simulations with prescriptions for cooling, star formation, stellar feedback, and galactic winds. This model galaxy moves through a constant density and temperature gas, which has parameters similar to the intra-cluster medium (ICM). Rotation curves (RCs) and 2D velocity fields of the gas are extracted from these simulations in a way that follows the procedure applied to observations of distant, small, and faint galaxies as closely as possible. We find that the appearance of distortions of the gaseous disc due to ram-pressure stripping depends on the direction of the acting ram pressure. In the case of face-on ram pressure, the distortions mainly appear in the outer parts of the galaxy in a very symmetric way. In contrast, in the case of edge-on ram pressure we find stronger distortions. The 2D velocity field also shows signatures of the interaction in the inner part of the disc. At angles smaller than 45 degrees between the ICM wind direction and the disc, the velocity field asymmetry increases significantly compared to larger angles. Compared to distortions caused by tidal interactions, the effects of ram-pressure stripping on the velocity field are relatively low in all cases and difficult to observe at intermediate redshift in seeing-limited observations. (abridged)Comment: 9 pages, 11 figures, accepted for publication in A&

Computational and Experimental Studies of Substrate Binding, Conformational Change and Importance of the Trimeric State in the Glycine Betaine Transporter BetP

The glycine betaine/sodium symporter BetP responds to changes in external osmolality by regulation of its transport activity. A recent X-ray structure of BetP confirms that it is a homotrimer and in this structure each protomer adopts an identical conformation, in which the pathway is occluded from both sides. Despite the availability of a wealth of experimental data for BetP, the structures of the alternate states (e.g., open to the outside of the cell), molecular mechanisms of substrate and Na⁺ binding and transport, as well as the functional implications of the trimeric state remain poorly understood. To address these questions, we carried out computational studies using a range of techniques to derive hypotheses that were then tested experimentally. First, to identify structural features of the alternate states, we developed a procedure for flexible fitting of the X-ray structure of BetP into a lower-resolution cryo-EM map of BetP in a more native lipid environment, in which the three protomers have different conformations. These results suggest that: (i) the protomers adopt distinct conformational states relevant to the transport cycle; and (ii) there is conformational coupling between the protomers. Second, we performed all-atom molecular dynamics simulations and in silico alanine scanning of BetP trimers in order to identify interface residues crucial for maintaining the trimeric state. Mutations of these residues to alanine were introduced experimentally revealing that the isolated monomers are functional, and that the trimeric state is important for the regulation and higher activity of the protein. Finally, using molecular modeling and biochemical experiments we identified two Na⁺ binding sites in BetP that could not be resolved in the 3.35 Å resolution X-ray structure

Development and initial validation of the Falls Efficacy Scale-International (FES-I)

Background: there is a need for a measure of fear of falling that assesses both easy and difficult physical activities and social activities and is suitable for use in a range of languages and cultural contexts, permitting direct comparison between studies and populations in different countries and settings. Objective: to develop a modified version of the Falls Efficacy Scale to satisfy this need, and to establish its psychometric properties, reliability, and concurrent validity (i.e. that it demonstrates the expected relationship with age, falls history and falls risk factors). Design: cross-sectional survey. Setting: community sample. Method: 704 people aged between 60 and 95 years completed The Falls Efficacy Scale-International (FES-I) either in postal self-completion format or by structured interview. Results: the FES-I had excellent internal and test-retest reliability (Cronbach's α=0.96, ICC=0.96). Factor analysis suggested a unitary underlying factor, with two dimensions assessing concern about less demanding physical activities mainly in the home, and concern about more demanding physical activities mainly outside the home. The FES-I had slightly better power than the original FES items to discriminate differences in concern about falling between groups differentiated by sex, age, occupation, falls in the past year, and falls risk factors (chronic illness, taking multiple or psychoactive medications, dizziness). Conclusions: the FES-I has close continuity with the best existing measure of fear of falling, excellent psychometric properties, and assesses concerns relating to basic and more demanding activities, both physical and social. Further research is required to confirm cross-cultural and predictive validit

Patient and professional experiences of palliative care referral discussions from cancer services : a qualitative interview study

Objectives The aim of this paper was to identify current barriers, facilitators and experiences of raising and discussing palliative care with people with advanced cancer. Methods Semi‐structured interviews were conducted with patients with advanced cancer and healthcare professionals (HCPs). Patients were included who had and had not been referred to palliative care. Transcripts were analysed using framework analysis. Results Twenty‐four patients and eight HCPs participated. Two overarching themes and five sub‐themes emerged: Theme one—referral process: timing and triggers, responsibility. Theme two—engagement: perception of treatment, prognosis and palliative care, psychological and emotional preparedness for discussion, and understanding how palliative care could benefit present and future care. Conclusion There is a need to identify suitable patients earlier in their cancer trajectory, address misconceptions about palliative care, treatment and prognosis, and better prepare patients and HCPs to have meaningful conversations about palliative care. Patients and HCPs need to establish and communicate the relevance of palliative care to the patient's current and future care, and be clear about the referral process

Role of N-glycosylation in renal betaine transport

The osmolyte and folding chaperone betaine is transported by the renal Na+-coupled GABA (γ-aminobutyric acid) symporter BGT-1 (betaine/GABA transporter 1), a member of the SLC6 (solute carrier 6) family. Under hypertonic conditions, the transcription, translation and plasma membrane (PM) insertion of BGT-1 in kidney cells are significantly increased, resulting in elevated betaine and GABA transport. Re-establishing isotonicity involves PM depletion of BGT-1. The molecular mechanism of the regulated PM insertion of BGT-1 during changes in osmotic stress is unknown. In the present study, we reveal a link between regulated PM insertion and N-glycosylation. Based on homology modelling, we identified two sites (Asn171 and Asn183) in the extracellular loop 2 (EL2) of BGT-1, which were investigated with respect to trafficking, insertion and transport by immunogold-labelling, electron microscopy (EM), mutagenesis and two-electrode voltage clamp measurements in Xenopus laevis oocytes and uptake of radiolabelled substrate into MDCK (Madin–Darby canine kidney) and HEK293 (human embryonic kidney) cells. Trafficking and PM insertion of BGT-1 was clearly promoted by N-glycosylation in both oocytes and MDCK cells. Moreover, association with N-glycans at Asn171 and Asn183 contributed equally to protein activity and substrate affinity. Substitution of Asn171 and Asn183 by aspartate individually caused no loss of BGT-1 activity, whereas the double mutant was inactive, suggesting that N-glycosylation of at least one of the sites is required for function. Substitution by alanine or valine at either site caused a dramatic loss in transport activity. Furthermore, in MDCK cells PM insertion of N183D was no longer regulated by osmotic stress, highlighting the impact of N-glycosylation in regulation of this SLC6 transporter

Helicobacter pylori and cancer among adults in Uganda

Data from Africa on infection with Helicobacter pylori (H. pylori) are sparse. Therefore, as part of an epidemiological study of cancer in Uganda, we investigated the prevalence and determinants of antibodies against H. pylori among 854 people with different cancer types and benign tumours. Patients were recruited from hospitals in Kampala, Uganda, interviewed about various demographic and lifestyle factors and tested for antibodies against H. pylori. In all patients combined, excluding those with stomach cancer (which has been associated with H. pylori infection), the prevalence of antibodies was 87% (723/833) overall, but declined with increasing age (p = 0.02) and was lower among people who were HIV seropositive compared to seronegative (p <0.001). Otherwise, there were few consistent epidemiological associations. Among those with stomach cancer, 18/21 (86%) had anti-H. pylori antibodies (odds ratio 0.8, 95% confidence intervals 0.2–2.9, p = 0.7; estimated using all other patients as controls, with adjustment for age, sex and HIV serostatus). No other cancer site or type was significantly associated with anti-H. pylori antibodies. The prevalence of H. pylori reported here is broadly in accord with results from other developing countries, although the determinants of infection and its' role in the aetiology of gastric cancer in Uganda remain unclear

Protostellar collapse: A comparison between SPH and AMR calculations

The development of parallel supercomputers allows today the detailed study of the collapse and the fragmentation of prestellar cores with increasingly accurate numerical simulations. Thanks to the advances in sub-millimeter observations, a wide range of observed initial conditions enable us to study the different modes of low-mass star formation. The challenge for the simulations is to reproduce the observational results. Two main numerical methods, namely AMR and SPH, are widely used to simulate the collapse and the fragmentation of prestellar cores. We compare thoroughly these two methods within their standard framework. We use the AMR code RAMSES and the SPH code DRAGON. Our physical model is as simple as possible and consists of an isothermal sphere rotating around the z-axis. We first study the conservation of angular momentum as a function of the resolution. Then, we explore a wide range of simulation parameters to study the fragmentation of prestellar cores. There seems to be a convergence between the two methods, provided resolution in each case is sufficient. Resolution criteria adapted to our physical cases, in terms of resolution per Jeans mass, for an accurate description of the formation of protostellar cores are deduced from the present study. This convergence is encouraging for future work in simulations of low-mass star formation, providing the aforementioned criteria are fulfilled. Higher resolution figures can be downloaded at http://www-dapnia.cea.fr/Projets/COAST/paper_amrvssph.pdfComment: 16 pages, 16 figures, accepted for publication in A&