The zinc finger transcription factor PLAGL2 enhances stem cell fate and activates expression of ASCL2 in intestinal epithelial cells

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Inpatient use and area-level socio-environmental factors in people with psychosis

Purpose: There is consistent evidence that socio-environmental factors measured at an area-level, such as ethnic density, urban environment and deprivation are associated with psychosis risk. However, whether area-level socio-environmental factors are associated with outcomes following psychosis onset is less clear. This study aimed to examine whether the number of inpatient days used by people presenting to mental health services for psychosis was associated with five key area-level socio-environmental factors: deprivation, ethnic density, social capital, population density and social fragmentation. Methods: Using a historical cohort design based on electronic health records from the South London and Maudsley NHS Trust Foundation electronic Patient Journey System, people who presented for the first time to SLAM between 2007 and 2010 with psychosis were included. Structured data were extracted on age at presentation, gender, ethnicity, residential area at first presentation and number of inpatient days over 5 years of follow-up. Data on area-level socio-environmental factors taken from published sources were linked to participants’ residential addresses. The relationship between the number of inpatient days and each socio-environmental factor was investigated in univariate negative binomial regression models with time in contact with services treated as an offset variable. Results: A total of 2147 people had full data on area level outcomes and baseline demographics, thus, could be included in the full analysis. No area-level socio-environmental factors were associated with inpatient days. Conclusion: Although a robust association exists between socio-environmental factors and psychosis risk, in this study we found no evidence that neighbourhood deprivation was linked to future inpatient admissions following the onset of psychosis. Future work on the influence of area-level socio-environmental factors on outcome should examine more nuanced outcomes, e.g. recovery, symptom trajectory, and should account for key methodological challenges, e.g. accounting for changes in address

Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27

Baseline patient and tumor characteristics differentially affected type of death in the MA.17 placebo-controlled letrozole trial where cardiovascular death was not separately identified. The MA.27 trial allowed competing risks analysis of breast cancer (BC), cardiovascular, and other type (OT) of death. MA.27 was a phase III adjuvant breast cancer trial of exemestane versus anastrozole. Effects of baseline patient and tumor characteristics were tested for whether factors were associated with (1) all cause mortality and (2) cause-specific mortality. We also fit step-wise forward cause-specific-adjusted models. 7576 women (median age 64 years; 5417 (72 %) < 70 years and 2159 (28 %) ≥ 70 years) were enrolled and followed for median 4.1 years. The 432 deaths comprised 187 (43 %) BC, 66 (15 %) cardiovascular, and 179 (41 %) OT. Five baseline factors were differentially associated with type of death. Older patients had greater BC (p = 0.03), cardiovascular (p < 0.001), and other types (p < 0.001) of mortality. Patients with pre-existing cardiovascular history had worse cardiovascular mortality (p < 0.001); those with worse ECOG performance status had worse OT mortality (p < 0.001). Patients with T1 tumors (p < 0.001) and progesterone receptor positive had less BC mortality (p < 0.001). Fewer BC deaths occurred with node-negative disease (p < 0.001), estrogen receptor-positive tumors (p = 0.001), and without adjuvant chemotherapy (p = 0.005); worse cardiovascular mortality (p = 0.01), with trastuzumab; worse OT mortality, for non-whites (p = 0.03) and without adjuvant radiotherapy (p = 0.003). Overall, 57 % of deaths in MA.27 AI-treated patients were non-breast cancer related. Baseline patient and tumor characteristics differentially affected type of death with women 70 or older experiencing more non-breast cancer death

Thermal constraints on the reionisation of hydrogen by population-II stellar sources

Measurements of the intergalactic medium (IGM) temperature provide a potentially powerful constraint on the reionisation history due to the thermal imprint left by the photo-ionisation of neutral hydrogen. However, until recently IGM temperature measurements were limited to redshifts 2 < z < 4.8, restricting the ability of these data to probe the reionisation history at z > 6. In this work, we use recent measurements of the IGM temperature in the near-zones of seven quasars at z ~ 5.8 - 6.4, combined with a semi-numerical model for inhomogeneous reionisation, to establish new constraints on the redshift at which hydrogen reionisation completed. We calibrate the model to reproduce observational constraints on the electron scattering optical depth and the HI photo-ionisation rate, and compute the resulting spatially inhomogeneous temperature distribution at z ~ 6 for a variety of reionisation scenarios. Under standard assumptions for the ionising spectra of population-II sources, the near-zone temperature measurements constrain the redshift by which hydrogen reionisation was complete to be z > 7.9 (6.5) at 68 (95) per cent confidence. We conclude that future temperature measurements around other high redshift quasars will significantly increase the power of this technique, enabling these results to be tightened and generalised.Comment: 15 pages, 8 figures, accepted for publication in MNRA

Beings in their own right? Exploring Children and young people's sibling and twin relationships in the Minority World

This paper examines the contributions that the sociological study of sibship and twinship in the Minority World can make to childhood studies. It argues that, in providing one forum within which to explore children and young people's social relationships, we can add to our understanding of children and young people's interdependence and develop a more nuanced understanding of agency. As emergent subjects, children, young people and adults are in a process of ‘becoming’. However, this does not mean that they can ‘become’ anything they choose to. The notion of negotiated interdependence (Punch 2002) is useful in helping us to grasp the contingent nature of children and young people's agency

Near and Mid-IR Photometry of the Pleiades, and a New List of Substellar Candidate Members

We make use of new near and mid-IR photometry of the Pleiades cluster in order to help identify proposed cluster members. We also use the new photometry with previously published photometry to define the single-star main sequence locus at the age of the Pleiades in a variety of color-magnitude planes. The new near and mid-IR photometry extend effectively two magnitudes deeper than the 2MASS All-Sky Point Source catalog, and hence allow us to select a new set of candidate very low mass and sub-stellar mass members of the Pleiades in the central square degree of the cluster. We identify 42 new candidate members fainter than Ks =14 (corresponding to 0.1 Mo). These candidate members should eventually allow a better estimate of the cluster mass function to be made down to of order 0.04 solar masses. We also use new IRAC data, in particular the images obtained at 8 um, in order to comment briefly on interstellar dust in and near the Pleiades. We confirm, as expected, that -- with one exception -- a sample of low mass stars recently identified as having 24 um excesses due to debris disks do not have significant excesses at IRAC wavelengths. However, evidence is also presented that several of the Pleiades high mass stars are found to be impacting with local condensations of the molecular cloud that is passing through the Pleiades at the current epoch.Comment: Accepted to ApJS; data tables and embedded-figure version available at http://spider.ipac.caltech.edu/staff/stauffer/pleiades07

Atomic Resonance and Scattering

Contains reports on four research projects.U.S. Air Force - Office of Scientific Research (Grant AFOSR-76-2972)National Science Foundation (Grant CHE79-02967)National Science Foundation (Grant PHY79-09743)Joint Services Electronics Program (Contract DAAG29-78-C-0020)Joint Services Electronics Program (Contract DAAG29-80-C-0104

Balancing mcr-1 expression and bacterial survival is a delicate equilibrium between essential cellular defence mechanisms

MCR-1 is a lipid A modifying enzyme that confers resistance to the antibiotic colistin. Here, we analyse the impact of MCR-1 expression on E. coli morphology, fitness, competitiveness, immune stimulation and virulence. Increased expression of mcr-1 results in decreased growth rate, cell viability, competitive ability and significant degradation in cell membrane and cytoplasmic structures, compared to expression of catalytically inactive MCR-1 (E246A) or MCR-1 soluble component. Lipopolysaccharide (LPS) extracted from mcr-1 strains induces lower production of IL-6 and TNF, when compared to control LPS. Compared to their parent strains, high-level colistin resistance mutants (HLCRMs) show reduced fitness (relative fitness is 0.41–0.78) and highly attenuated virulence in a Galleria mellonella infection model. Furthermore, HLCRMs are more susceptible to most antibiotics than their respective parent strains. Our results show that the bacterium is challenged to find a delicate equilibrium between expression of MCR-1-mediated colistin resistance and minimalizing toxicity and thus ensuring cell survival

Randomized Trial of Letrozole Following Tamoxifen as Extended Adjuvant Therapy in Receptor-Positive Breast Cancer: Updated Findings from NCIC CTG MA.17

Background: Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial. Methods: Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan-Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided. Results: After a median follow-up of 30 months (range = 1.5-61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confidence interval [CI] = 0.45 to 0.76; P<.001; distant DFS: HR = 0.60, 95% CI = 0.43 to 0.84; P = .002). Overall survival was the same in both arms (HR for death from any cause = 0.82, 95% CI = 0.57 to 1.19; P = .3). However, among lymph node-positive patients, overall survival was statistically significantly improved with letrozole (HR = 0.61, 95% CI = 0.38 to 0.98; P = .04). The incidence of contralateral breast cancer was lower in women receiving letrozole, but the difference was not statistically significant. Women receiving letrozole experienced more hormonally related side effects than those receiving placebo, but the incidences of bone fractures and cardiovascular events were the same. Conclusion: Letrozole after tamoxifen is well-tolerated and improves both disease-free and distant disease-free survival but not overall survival, except in node-positive patient

Population genomics of domestic and wild yeasts

The natural genetics of an organism is determined by the distribution of sequences of its genome. Here we present one- to four-fold, with some deeper, coverage of the genome sequences of over seventy isolates of the domesticated baker&#x27;s yeast, _Saccharomyces cerevisiae_, and its closest relative, the wild _S. paradoxus_, which has never been associated with human activity. These were collected from numerous geographic locations and sources (including wild, clinical, baking, wine, laboratory and food spoilage). These sequences provide an unprecedented view of the population structure, natural (and artificial) selection and genome evolution in these species. Variation in gene content, SNPs, indels, copy numbers and transposable elements provide insights into the evolution of different lineages. Phenotypic variation broadly correlates with global genome-wide phylogenetic relationships however there is no correlation with source. _S. paradoxus_ populations are well delineated along geographic boundaries while the variation among worldwide _S. cerevisiae_ isolates show less differentiation and is comparable to a single _S. paradoxus_ population. Rather than one or two domestication events leading to the extant baker&#x27;s yeasts, the population structure of _S. cerevisiae_ shows a few well defined geographically isolated lineages and many different mosaics of these lineages, supporting the notion that human influence provided the opportunity for outbreeding and production of new combinations of pre-existing variation