Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer

In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.

The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer

BACKGROUND: Lapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination.

PATIENTS AND METHODS: DNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher's exact test, Kaplan-Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate.

RESULTS: There were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92).

CONCLUSION: Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.

Meta-analysis of Positive and Negative Symptoms Reveals Schizophrenia Modifier Genes

BACKGROUND: Evidence suggests that genetic factors may influence both schizophrenia (Scz) and its clinical presentation. In recent years, genome-wide association studies (GWAS) have demonstrated considerable success in identifying risk loci. Detection of "modifier loci" has the potential to further elucidate underlying disease processes.

METHODS: We performed GWAS of empirically derived positive and negative symptom scales in Irish cases from multiply affected pedigrees and a larger, independent case-control sample, subsequently combining these into a large Irish meta-analysis. In addition to single-SNP associations, we considered gene-based and pathway analyses to better capture convergent genetic effects, and to facilitate biological interpretation of these findings. Replication and testing of aggregate genetic effects was conducted using an independent European-American sample.

RESULTS: Though no single marker met the genome-wide significance threshold, genes and ontologies/pathways were significantly associated with negative and positive symptoms; notably, NKAIN2 and NRG1, respectively. We observed limited overlap in ontologies/pathways associated with different symptom profiles, with immune-related categories over-represented for negative symptoms, and addiction-related categories for positive symptoms. Replication analyses suggested that genes associated with clinical presentation are generalizable to non-Irish samples.

CONCLUSIONS: These findings strongly support the hypothesis that modifier loci contribute to the etiology of distinct Scz symptom profiles. The finding that previously implicated "risk loci" actually influence particular symptom dimensions has the potential to better delineate the roles of these genes in Scz etiology. Furthermore, the over-representation of distinct gene ontologies/pathways across symptom profiles suggests that the clinical heterogeneity of Scz is due in part to complex and diverse genetic factors.

Alcohol use and positive screening results for depression and anxiety are highly prevalent among chinese children with strabismus

Purpose: To study associations between strabismus and alcohol use, anxiety, and depression among 10- to 17-year-old children in Guangdong, southern China. Design: Cross-sectional, population-based study. Methods: Among 7537 children aged 6-17 years from 9 randomly selected primary and middle schools, ocular alignment was assessed with the Hirschberg light reflex, cover-uncover testing, and alternate cover testing at distance (6 m) and near (40 cm). Additionally, 4000 children (53.1%) aged 10+ years received self-administered questionnaires containing screening questions on alcohol use, anxiety, and depression. Results: Examinations were completed on 7464 of 7537 subjects (99.0%), including 3928 boys (52.6%), with a mean age of 11.1 ± 1.8 years. The prevalence of any strabismus, including exotropia (2.7%), esotropia (0.2%), and intermittent exotropia (3.9%), was 6.8%. Strabismus was more prevalent in urban students (7.3%) and female subjects (7.4%) compared to rural students (6.0%) and male subjects (6.2%) (all P <.05). In multivariate regression models, any strabismus was associated with older age and rural vs urban residence. Among 3903 children (97.6%) answering questionnaires, history of alcohol use (62.3% vs 36.3%) and positive screening responses for depression (26.0% vs 11.6%) and anxiety (10.3% vs 4.9%) were significantly (P <.01 for all) more common among children with strabismus. Conclusion: These Chinese children with strabismus had a significantly higher prevalence of alcohol use and possible markers of emotional problems than children without strabismus. Further research should focus on the appropriateness of classifying surgical treatment for strabismus as "cosmetic" (ineligible for reimbursement) under China's rural health insurance.

The Legitimacy of Subsidiary Issue Selling: Balancing Positive & Negative Attention from Corporate Headquarters

We consider how in issue selling, subsidiaries draw on different forms of legitimacy to attract corporate headquarters’ (CHQ) positive attention and minimise negative CHQ attention. Through case study evidence, we find that directing CHQ attention to subsidiary issues needs to be executed as a balancing act through forms of subsidiary legitimacy, namely; the personal legitimacy of key individuals at the subsidiary; consequential legitimacy vis-à-vis peer subsidiaries; and linkage legitimacy in the local environment. We develop a typology of subsidiary issue-selling roles and illustrate how negative CHQ attention results from a failure to legitimise issue selling.

A high-value, low-cost bubble continuous positive airway pressure system for low-resource settings:technical assessment and initial case reports

Acute respiratory infections are the leading cause of global child mortality. In the developing world, nasal oxygen therapy is often the only treatment option for babies who are suffering from respiratory distress. Without the added pressure of bubble Continuous Positive Airway Pressure (bCPAP) which helps maintain alveoli open, babies struggle to breathe and can suffer serious complications, and frequently death. A stand-alone bCPAP device can cost $6,000, too expensive for most developing world hospitals. Here, we describe the design and technical evaluation of a new, rugged bCPAP system that can be made in small volume for a cost-of-goods of approximately $350. Moreover, because of its simple design--consumer-grade pumps, medical tubing, and regulators--it requires only the simple replacement of a <$1 diaphragm approximately every 2 years for maintenance. The low-cost bCPAP device delivers pressure and flow equivalent to those of a reference bCPAP system used in the developed world. We describe the initial clinical cases of a child with bronchiolitis and a neonate with respiratory distress who were treated successfully with the new bCPAP device.

Electron impact fragmentation of thymine:partial ionization cross sections for positive fragments

We have measured mass spectra for positive ions for low-energy electron impact on thymine using a reflectron time-of-flight mass spectrometer. Using computer controlled data acquisition, mass spectra have been acquired for electron impact energies up to 100 eV in steps of 0.5 eV. Ion yield curves for most of the fragment ions have been determined by fitting groups of adjacent peaks in the mass spectra with sequences of normalized Gaussians. The ion yield curves have been normalized by comparing the sum of the ion yields to the average of calculated total ionization cross sections. Appearance energies have been determined. The nearly equal appearance energies of 83 u and 55 u observed in the present work strongly indicate that near threshold the 55 u ion is formed directly by the breakage of two bonds in the ring, rather than from a successive loss of HNCO and CO from the parent ion. Likewise 54 u is not formed by CO loss from 82 u. The appearance energies are in a number of cases consistent with the loss of one or more hydrogen atoms from a heavier fragment, but 70 u is not formed by hydrogen loss from 71 u.

The effectiveness of peer mentoring in promoting a positive transition to higher education for first-year undergraduate students: a mixed methods systematic review protocol

Background: The global transfer of nursing and midwifery education to higher education institutes has led to student nurses and midwives experiencing challenges previously faced by traditional third-level students, including isolation, loneliness, financial difficulties and academic pressure. These challenges can contribute to increased stress and anxiety levels which may be detrimental to the successful transition to higher education, thus leading to an increase in attrition rates. Peer mentoring as an intervention has been suggested to be effective in supporting students in the transition to third-level education through enhancing a sense of belongingness and improving student satisfaction, engagement and retention rates. This proposed systematic review aims to determine the effectiveness of peer mentoring in enhancing levels of student engagement, sense of belonging and overall satisfaction of first-year undergraduate students following transition into higher education.
Methods: MEDLINE, Web of Knowledge, ProQuest, Embase, CINAHL, ERIC, PsycINFO and CENTRAL databases will be searched for qualitative, quantitative and mixed methods studies on the implementation of peer assessment strategies in higher education institutes (HEIs) or universities for full-time, first-year adult students (>17 years). Included studies will be limited to the English language. The quality of included studies will be assessed using a validated Mixed Methods Appraisal Tool (MMAT). The findings will be presented as a narrative synthesis or meta-analysis as appropriate following sequential explanatory synthesis.
Discussion: The review will provide clear, non-biased evidence-based guidance to all third-level educators on the effectiveness of peer-mentoring programmes for first-year undergraduates. The review is necessary to help establish which type of peer mentoring is most effective. The evidence from qualitative and quantitative studies drawn from the international literature will be utilised to illustrate the best way to implement and evaluate peer mentoring as an effective intervention and will be useful in guiding future research and practice in this area. These findings may be applied internationally across all disciplines.

Perceived positive and negative consequences after surviving cancer and their relation to quality of life

Surviving childhood cancer has multiple implications on both physical and psychological domains of the individual. However, its study and possible effects on health-related quality of life (HRQoL) outcomes of adolescent survivors has been understudied. The objective of this study was twofold; to assess positive and negative cancer-related consequences (psychosocial and physical) in a sample of adolescent cancer survivors and to explore their relationship with HRQoL outcomes. Forty-one participants answered two questions about positive and negative consequences in the aftermath of cancer and filled in the KIDSCREEN-52 self-reported version. Data were analysed using mixed methods approach. 87.8% of the sample identified positive consequences and 63.4% negative consequences in survivorship. Four positive categories and five negative categories with regard to cancer-related consequences were found. Changed perspectives in life narratives seem to be the positive consequence more related to HRQoL (physical well-being, mood & emotions, autonomy, social support & peers), followed by useful life experience (physical well-being, autonomy, social support & peers). Psychological impact was the most referred negative consequence with a significant detrimental effect on social support and peers HRQoL dimension. Even if the majority of survivors reported benefit finding in the aftermath of cancer, concomitant positive and negative consequences have been found. However, findings only reveal a significant relationship between positive narratives and HRQoL, and negative consequences do not seem to have a significant influence on overall HRQoL in survivorship.

HIV positive men as fathers: Accounts of displacement, ir/responsibility and paternal emergence

It is now apparent that socio-cultural constructions of masculinity variously impact men’s experiences of their HIV positive status, yet how being a father can feature in this mix remains under-researched. This study employed in-depth semi-structured interviews and Foucauldian-informed discourse analysis to explore the accounts of six self-identifying heterosexual fathers (four black African migrants, two white European) who had been living with HIV from five to 24 years. While the HIV-related literature calls for the need to subvert ‘traditional’ expressions of masculinity as a means of promoting HIV prevention and HIV health, we argue that the lived experience for HIV positive men as fathers is more socially, discursively and thus more psychologically nuanced. We illustrate this by highlighting ways in which HIV positive men as fathers are not simply making sense of themselves as a HIV positive man for whom the modern (new) man and father positions are useful strategies for adapting to HIV and combating associated stigma. Discourses of modern and patriarchal fatherhoods, a gender-specific discourse of irresponsibility, and the neoliberal conflation of heath and self-responsibility are also at work in the sense making frames that HIV positive men, who are also fathers, can variously deploy. Our analysis shows how this discursive mix can underpin possibilities of often conflicted meaning and identity when living as a man and father with HIV in the UK, and specifically how discourses of fatherhood and HIV ‘positive’ health can complicate these men’s expressions and inhabitations of masculinity.

Second Wave Positive Psychology: Exploring the Positive–Negative Dialectics of Wellbeing

Positive psychology has tended to be defined in terms of a concern with ‘positive’ psychological qualities and states. However, critics of the field have highlighted various problems inherent in classifying phenomena as either ‘positive’ or ‘negative.’ For instance, ostensibly positive qualities (e.g., optimism) can sometimes be detrimental to wellbeing, whereas apparently negative processes (like anxiety) may at times be conducive to it. As such, over recent years, a more nuanced ‘second wave’ of positive psychology has been germinating, which explores the philosophical and conceptual complexities of the very idea of the ‘positive.’ The current paper introduces this emergent second wave by examining the ways in which the field is developing a more subtle understanding of the ‘dialectical’ nature of flourishing (i.e., involving a complex and dynamic interplay of positive and negative experiences). The paper does so by problematizing the notions of positive and negative through seven case studies, including five salient dichotomies (such as optimism versus pessimism) and two complex processes (posttraumatic growth and love). These case studies serve to highlight the type of critical, dialectical thinking that characterises this second wave, thereby outlining the contours of the evolving field.

‘Not like rose-tinted glasses… like taking a pair of dirty glasses off’: A pilot intervention using positive emotions in expressive writing

Studies conducted in various contexts and with varied populations have found expressive writing enhances physical and psychological wellbeing. This pilot intervention study countered the predominantly quantitative evidence by adopting a qualitative methodology, exploring the experience of using positive emotions in expressive writing. Participants (n = 10), who all had previous experience in expressive writing, were asked to select one of ten positive emotion cards (PECs) each day for three days. Participants were then asked to write expressively through the ‘lens’ of their chosen emotion. Semi-structured interviews were conducted and experiences were evaluated using Thematic Analysis. The results identified two main themes that compared the experience of expressive writing both with and without the PECs. The first theme, Processing (without the PECs) contained three sub-themes: sense of relief, habitual perspective and reactive to experience. The second main theme, Progressing (with the PECs) contained three different sub-themes: sense of direction, changed perspective and interactive with experience. This study found that, for expressive writers, positive emotions may function in three ways: to relate to others or self-expand, to move past challenges cognitively or change unconstructive perspectives, and finally as a way to interactively link or ‘bridge’ from the written subject matter to constructive action, thus breaking cycles of reactive writing and rumination. Implications of the study on the practice of expressive writing and its potential as a positive psychology intervention (PPI) are discussed.

Towards a positive cross-cultural lexicography: Enriching our emotional landscape through 216 ‘untranslatable’ words pertaining to well-being

Although much attention has been paid to culture-specific psychopathologies, there have been no comparable attempts to chart positive mental states that may be particular to certain cultures. This paper outlines the beginnings of a positive cross-cultural lexicography of ‘untranslatable’ words pertaining to wellbeing, culled from across the world’s languages. A quasi-systematic search uncovered 216 such terms. Using grounded theory, these words were organised into three categories: feelings (comprising positive and complex feelings); relationships (comprising intimacy and pro-sociality); and character (comprising personal resources and spirituality). The paper has two main aims. First, it aims to provide a window onto cultural differences in constructions of wellbeing, thereby enriching our understanding of wellbeing. Second, a more ambitious aim is that this lexicon may help expand the emotional vocabulary of English speakers (and indeed speakers of all languages), and consequently enrich their experiences of wellbeing. The paper concludes by setting out a research agenda to pursue these aims further.