A novel ecological methodology for constructing ethnic-majority life tables in the absence of individual ethnicity information.

BACKGROUND: Deprivation-specific life tables have been in use for some time, but health outcomes are also known to vary by ethnicity over and above deprivation. The mortality experiences of ethnic groups are little studied in the UK, however, because ethnicity is not captured on death certificates. METHODS: Population data for all Output Areas (OAs) in England and Wales were stratified by age-group, sex and ethnic proportion, and matched to the deaths counts in that OA from 2000 to 2002. We modelled the relationship between mortality, age, deprivation and ethnic proportion. We predicted mortality rates for an area that contained the maximum proportion of each ethnic group reported in any area in England and Wales, using a generalised linear model with a Poisson distribution adjusted for deprivation. RESULTS: After adjustment, Asian and White life expectancies between 1 and 80 years were very similar. Black men and women had lower life expectancies: men by 4 years and women by around 1.5 years. The Asian population had the lowest mortality of all groups over age 45 in women and over 50 in men, whereas the Black population had the highest rates throughout, except in girls under 15. CONCLUSIONS: We adopted a novel ecological method of constructing ethnic-majority life tables, adjusted for deprivation. There is still diversity within these three broad ethnic groups, but our data show important residual differences in mortality for Black men and women. These ethnic life tables can be used to inform public health planning and correctly account for background mortality in ethnic subgroups of the population

What might explain deprivation-specific differences in the excess hazard of breast cancer death amongst screen-detected women? Analysis of patients diagnosed in the West Midlands region of England from 1989 to 2011.

BACKGROUND: Breast cancer survival is higher in less deprived women, even amongst women whose tumor was screen-detected, but reasons behind this have not been comprehensively investigated. METHODS: The excess hazard of breast cancer death in 20,265 women diagnosed with breast cancer, followed up to 2012, was estimated for screen-detected and non-screen-detected women, comparing more deprived to less deprived women using flexible parametric models. Models were adjusted for individual and tumor factors, treatment received and comorbidity. For screen-detected women, estimates were also corrected for lead-time and overdiagnosis. RESULTS: The excess hazard ratio (EHR) of breast cancer death in the most deprived group, adjusted only for age and year of diagnosis, was twice that of the least deprived among screen-detected women (EHR=2.12, 95%CI 1.48-2.76) and 64% higher among non-screen-detected women (EHR=1.64, 95%CI 1.41-1.87). Adjustment for stage at diagnosis lowered these estimates by 25%. Further adjustment had little extra impact. In the final models, the excess hazard for the most deprived women was 54% higher (EHR=1.54, 95%CI 1.10-1.98) among screen-detected women and 39% higher (EHR=1.39, 95%CI 1.20-1.59) among non-screen-detected women. CONCLUSION: A persistent socio-economic gradient in breast cancer-related death exists in this cohort, even for screen-detected women. The impact of differential lifestyles, management and treatment warrant further investigation

Intrahepatic cholestasis of pregnancy is not associated with stillbirth in an Australian maternity population

Dissertação de mestrado em Relações Internacionais (Estudos da Paz e da Segurança), apresentada à Faculdade de Economia da Universidade de CoimbraNo seguimento de experiências de violência extrema, no contexto de regimes políticos autoritários e violações sistemáticas de direitos humanos, algumas sociedades são confrontadas com questões relativas ao legado desse passado de violência, cujo impacto se faz sentir diretamente ao nível dos seus processos de (re)conciliação e reconstrução pós-conflito: o que será lembrado e esquecido, na construção da memória e verdade(s) sobre o conflito, e na transmissão do conhecimento às gerações futuras? O que deve acontecer aos indivíduos que planearam e aos que exerceram a violência? Que tipo de crimes serão julgados? Que tipo de processos judiciais e mecanismos de reparação serão estabelecidos e com que propósitos? Como é que uma sociedade pode (re)estabelecer os seus laços sociais intra-comunitários e até que ponto é que indivíduos que se percecionam mutuamente como inimigos alguma vez se poderão reconciliar? Estas são questões relacionadas com o fenómeno de justiça de transição, que se tem vindo a estabelecer enquanto norma global para as sociedades lidarem com o passado. A justiça de transição não só é uma área pouco teorizada como a sua teoria e prática dependem, em larga medida, de pressupostos adquiridos e partilhados com o modelo liberal internacional de construção da paz (peacebuilding). Esta dissertação procura problematizar mais especificamente um destes pressupostos, a dicotomia “vítimaperpetrador” e os processos de categorização inerentes ao modelo dominante de justiça de transição, em geral, tal como este é pensado e implementado ao nível internacional e nacional. Com base no estudo de caso do Ruanda, o nosso objetivo é demonstrar as insuficiências e limitações desta visão dicotómica para interpretar dinâmicas profundas de conflito considerando, ao invés, a diversidade de experiências de violência e vitimização que esta dicotomia exclui e refletindo sobre o seu impacto nas perspectivas de (re)conciliação pós-conflito, em particular da sociedade Ruandesa. De forma a atingir o objetivo a que nos propomos, a análise desta dissertação será orientada pela seguinte pergunta de partida: de que forma, no contexto de sociedades pós-conflito, como o Ruanda, pode uma narrativa de vitimização dominante ser desafiada por excluir uma diversidade de experiências de vitimização e violência, e que repercussões pode esta contestação originar para as perspectivas de (re)conciliação nesta sociedade? A nossa análise estará alicerçada em três hipóteses: (i) a dicotomia “vítima-perpetrator” é um elemento fundamental das iniciativas de transição pós-conflito apoiados pela ONU e implementados no contexto de intervenções internacionais; (ii) o Ruanda no pósgenocídio é caracterizado por uma narrativa nacional dominante de vitimização, baseada numa dicotomia “vítima-perpetrator” que é insuficiente para compreender a diversidade de experiências de violência e vitimização vivida por diferentes grupos sociais, excluindoas e deslegitimando-as; e (iii) os processos de justiça de transição orientados segundo esta dicotomia provocam novas formas de re-vitimização, por um lado, invisibilizando e deslegitimando certas experiências de violência e vitimização e, por outro lado, tomando estas categorias socio-políticas como absolutas, limitando assim a agência política dos indivíduos e a sua (re)integração social, colocando em causa o processo de (re)conciliação em sociedades divididas em geral, e na Ruandesa em particular. A validação destas hipóteses será baseada numa abordagem qualitativa à investigação, com base na interpretação qualitativa de informação textual recolhida através de fontes primárias e secundárias, e também na análise de discurso. O enquadramento teórico e conceptual com base no qual articularemos a nossa crítica combina contributos teóricos de duas disciplinas distintas mas complementares: a psicologia social, mais precisamente o trabalho de Carlos Beristain sobre a abordagem psicosocial, e a teoria das relações internacionais, especificamente a vertente mais crítica da abordagem construtivista. Da nossa análise decorreu a validação das nossas hipóteses iniciais, sendo que demonstrámos assim como a dicotomia “vítima-perpetrator” se tem tornado um elemento fundamental nas iniciativas de justiça de transição apoiadas pela ONU; discutimos e detalhámos as narrativas dominantes de justiça de transição e vitimização estabelecidas no Ruanda e as suas dinâmicas de exclusão e, por último, refletimos sobre como os processos de justiça de transição orientados por esta dicotomia promovem processos de revitimização e limitam as perspectivas de longo prazo de reconciliação em sociedades divididas, como exemplificado pelo Ruanda no pós-genocídio.Following experiences of extreme violence, in the context of authoritarian political regimes and systematic human rights violations, societies are faced with questions regarding the legacy of that past of violence, which directly impact on the processes of (re)conciliation and post-conflict rebuilding: what will be remembered and forgotten, in the construction of memory and truth(s) relating to the conflict, and in the transmission of knowledge to younger generations? What should happen to those individuals who planned and those who enacted the violence? What will be the range of crimes under investigation? What kind of judicial processes and mechanisms for reparations will be established and with what purposes? How can a community (re)establish its social intra-community ties and to what extent and in which way can individuals who perceive each other as enemies ever reconcile? These questions fall within the scope of the phenomenon of transitional justice, which has been establishing itself as a global norm on how societies should deal with the past. Not only is the field of transitional justice under theorized but its dominant discourse on theory and praxis relies heavily on core assumptions taken for granted, many of which borrowed from liberal peacebuilding. Our dissertation seeks to problematize one of these, in particular, the “victim-perpetrator” dichotomy and the categorizing inherent to the dominant transitional justice model thought of and implemented at both international and national levels. Drawing on Rwanda as a case study, this dissertation will aim at demonstrating the insufficiencies and limitations of this dichotomised view in understanding deeper conflict dynamics, by looking into the diversity of violence and victimhood experiences that this dichotomy excludes and by reflecting upon its impact on the prospects of post-conflict (re)conciliation, specifically with regards to contemporary Rwandan society. In order to achieve our proposed aim, the analysis in this dissertation will be guided by the following research question: In what way, in the context of a post-conflict society such as Rwanda, can an established dominant victimhood narrative be challenged for excluding the diversity of victimization and violence experiences, and what repercussions may that dispute have on the prospects of (re)conciliation in this society? Our analysis will be grounded on three working hypotheses: (i) the dichotomy “victim-perpetrator” is a fundamental element in UN-sanctioned post-conflict transition Initiatives implemented in the context of international interventions; (ii) post -genocide Rwanda is characterized by a national dominant victimhood narrative, based on a “victim-perpetrator” dichotomy which is insufficient to understand the full diversity of violence and victimhood experiences from different social groups, therefore excluding and delegitimizing them; and (iii) transitional justice processes framed by this dichotomy promote new forms of victimization, on the one hand, by making invisible (and, therefore, illegitimate) certain experiences of violence and victimhood and, on the other hand, by essentializing these sociopolitical categories, which ends up limiting individuals’ political agency and social reintegration, hindering the reconciliation process in divided societies and, particularly, in Rwanda. The validation of these hypotheses will be based on a qualitative research approach, in this way relying on the qualitative interpretation of textual (qualitative) data collected both from the literature and from primary evidence as well as discourse analysis. The theoretical and conceptual framework supporting our critique combines contributions from two distinct but, complementary fields of study: social psychology, in particular the work of Carlos Beristain on the psychosocial approach, and international relations theory, drawing on the more critical strand of constructivism. Our discussion successfully validated our three initial hypotheses, therefore asserting how the “victim-perpetrator” dichotomy has become a fundamental element in UN-sanctioned transit ional justice initiatives; discussing and detailing the dominant transitional justice and victimhood narratives in Rwanda and their dynamics of exclusion and, finally, reflecting on how transitional justice processes framed by this dichotomy promote re-victimization and hinder long-term reconciliation in divided societies such as post-genocide Rwanda

Variation in hospital caesarean section rates for preterm births

Background: Evidence about optimal mode of delivery for preterm birth is lacking and there is thought to be considerable variation in practice. Objective: To assess whether variation in hospital preterm caesarean section rates (Robson Classification Group 10) and outcomes are explained by casemix, labour or hospital characteristics. Materials and Methods: Population-based cohort study in NSW, 2007-2011. Births were categorised according to degree of prematurity and hospital service capability: 26-31 weeks, 32-33 weeks and 34-36 weeks. Hospital preterm caesarean rates were investigated using multilevel logistic regression models, progressively adjusting for casemix, labour and hospital factors. The association between hospital caesarean rates, and severe maternal and neonatal morbidity rates was assessed. Results: At 26-31 weeks the caesarean rate was 55.2% (7 hospitals, range 43.4-58.4%); 50.9% at 32-33 weeks (12 hospitals, 43.4- 58.1%); and 36.4% at 34-36 weeks (51 hospitals, 17.4-48.3%). At 26-31 weeks and 32-33 weeks, 81% and 59% of the variation between hospitals was explained with no hospital significantly different from the state average after adjustment. At 34-36 weeks, although 59% of the variation was explained, substantial unexplained variation persisted. Hospital caesarean rates were not associated with severe maternal morbidity rates at any gestational age. At 26-31 weeks medium and high caesarean rates were associated with higher severe neonatal morbidity rates, but there was no evidence of this association ≥32 weeks. 3 Conclusion: Both casemix and practice differences contributed to the variation in hospital caesarean rates. Low preterm caesarean rates were not associated with worse outcomes.Australian National Health and Medical Research Council; Australian Research Counci

A Match Made in Heaven: Exploring Views of Medicine Students, Pharmacy Interns and Facilitators in an Interprofessional Medicines Pilot Study

Purpose: To date, few interprofessional education initiatives have included just medicine and pharmacy learners. This research sought to explore learners’ and facilitators’ views of an interprofessional education medicines pilot study involving medical students and pharmacy interns. Methods: Qualitative feedback was gathered from the participating learners and a facilitator focus group was undertaken. Results: Medical student and pharmacy intern learners reported enjoying taking part and found the simulation and overall initiative to be authentic. They described learning most about each other’s roles and responsibilities and about teamwork, collaborative management, and collaboration. Some logistical improvements were suggested. The facilitators judged that the topic of medicines, with medical and pharmacy learners taking part, to be a match made in heaven. Conclusions: Medical student and pharmacy intern learners found the medicines topic and discipline grouping facilitated their learning. Some topics and groups of disciplines are ideally matched for IPE and such a nexus should be capitalised upon

A Structural Basis for Cellular Uptake of GST-Fold Proteins

It has recently emerged that glutathione transferase enzymes (GSTs) and other structurally related molecules can be translocated from the external medium into many different cell types. In this study we aim to explore in detail, the structural features that govern cell translocation and by dissecting the human GST enzyme GSTM2-2 we quantatively demonstrate that the α-helical C-terminal domain (GST-C) is responsible for this property. Attempts to further examine the constituent helices within GST-C resulted in a reduction in cell translocation efficiency, indicating that the intrinsic GST-C domain structure is necessary for maximal cell translocation capacity. In particular, it was noted that the α-6 helix of GST-C plays a stabilising role in the fold of this domain. By destabilising the conformation of GST-C, an increase in cell translocation efficiency of up to ∼2-fold was observed. The structural stability profiles of these protein constructs have been investigated by circular dichroism and differential scanning fluorimetry measurements and found to impact upon their cell translocation efficiency. These experiments suggest that the globular, helical domain in the 'GST-fold' structural motif plays a role in influencing cellular uptake, and that changes that affect the conformational stability of GST-C can significantly influence cell translocation efficiency.This work was supported by Grant DP0558315 Australian Research Council (http://www.arc.gov.au/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Are socio-economic inequalities in breast cancer survival explained by peri-diagnostic factors?

BACKGROUND: Patients living in more deprived localities have lower cancer survival in England, but the role of individual health status at diagnosis and the utilisation of primary health care in explaining these differentials has not been widely considered. We set out to evaluate whether pre-existing individual health status at diagnosis and primary care consultation history (peri-diagnostic factors) could explain socio-economic differentials in survival amongst women diagnosed with breast cancer. METHODS: We conducted a retrospective cohort study of women aged 15-99 years diagnosed in England using linked routine data. Ecologically-derived measures of income deprivation were combined with individually-linked data from the English National Cancer Registry, Clinical Practice Research Datalink (CPRD) and Hospital Episodes Statistics (HES) databases. Smoking status, alcohol consumption, BMI, comorbidity, and consultation histories were derived for all patients. Time to breast surgery was derived for women diagnosed after 2005. We estimated net survival and modelled the excess hazard ratio of breast cancer death using flexible parametric models. We accounted for missing data using multiple imputation. RESULTS: Net survival was lower amongst more deprived women, with a single unit increase in deprivation quintile inferring a 4.4% (95% CI 1.4-8.8) increase in excess mortality. Peri-diagnostic co-variables varied by deprivation but did not explain the differentials in multivariable analyses. CONCLUSIONS: These data show that socio-economic inequalities in survival cannot be explained by consultation history or by pre-existing individual health status, as measured in primary care. Differentials in the effectiveness of treatment, beyond those measuring the inclusion of breast surgery and the timing of surgery, should be considered as part of the wider effort to reduce inequalities in premature mortality

Dependence on RAD52 and RAD1 for anticancer drug resistance mediated by inactivation of mismatch repair genes

AbstractMismatch repair (MMR) proteins repair mispaired DNA bases and have an important role in maintaining the integrity of the genome [1]. Loss of MMR has been correlated with resistance to a variety of DNA-damaging agents, including many anticancer drugs [2]. How loss of MMR leads to resistance is not understood, but is proposed to be due to loss of futile MMR activity and/or replication stalling [3,4]. We report that inactivation of MMR genes (MLH1, MLH2, MSH2, MSH3, MSH6, but not PMS1) in isogenic strains of Saccharomyces cerevisiae led to increased resistance to the anticancer drugs cisplatin, carboplatin and doxorubicin, but had no effect on sensitivity to ultraviolet C (UVC) radiation. Sensitivity to cisplatin and doxorubicin was increased in mlh1 mutant strains when the MLH1 gene was reintroduced, demonstrating a direct involvement of MMR proteins in sensitivity to these DNA-damaging agents. Inactivation of MLH1, MLH2 or MSH2 had no significant effect, however, on drug sensitivities in the rad52 or rad1 mutant strains that are defective in mitotic recombination and removing unpaired DNA single strands. We propose a model whereby MMR proteins – in addition to their role in DNA-damage recognition – decrease adduct tolerance during DNA replication by modulating the levels of recombination-dependent bypass. This hypothesis is supported by the finding that, in human ovarian tumour cells, loss of hMLH1 correlated with acquisition of cisplatin resistance and increased cisplatin-induced sister chromatid exchange, both of which were reversed by restoration of hMLH1 expression

Cigarette pack size and consumption: an adaptive randomised controlled trial.

BackgroundObservational evidence suggests that cigarette pack size - the number of cigarettes in a single pack - is associated with consumption but experimental evidence of a causal relationship is lacking. The tobacco industry is introducing increasingly large packs, in the absence of maximum cigarette pack size regulation. In Australia, the minimum pack size is 20 but packs of up to 50 cigarettes are available. We aimed to estimate the impact on smoking of reducing cigarette pack sizes from ≥25 to 20 cigarettes per pack.MethodA two-stage adaptive parallel group RCT in which Australian smokers who usually purchase packs containing ≥25 cigarettes were randomised to use only packs containing either 20 (intervention) or their usual packs (control) for four weeks. The primary outcome, the average number of cigarettes smoked per day, was measured through collecting all finished cigarette packs, labelled with the number of cigarettes participants smoked. An interim sample size re-estimation was used to evaluate the possibility of detecting a meaningful difference in the primary outcome.ResultsThe interim analysis, conducted when 124 participants had been randomised, suggested 1122 additional participants needed to be randomised for sufficient power to detect a meaningful effect. This exceeded pre-specified criteria for feasible recruitment, and data collection was terminated accordingly. Analysis of complete data (n = 79) indicated that the mean cigarettes smoked per day was 15.9 (SD = 8.5) in the intervention arm and 16.8 (SD = 6.7) among controls (difference - 0.9: 95%CI = - 4.3, 2.6).ConclusionIt remains unclear whether reducing cigarette pack sizes from ≥25 to 20 cigarettes reduces cigarette consumption. Importantly, the results of this study provide no evidence that capping cigarette pack sizes would be ineffective at reducing smoking. The limitations identified in this study can inform a more efficient RCT, which is urgently required to address the dearth of experimental evidence on the impact of large cigarette pack sizes on smoking.Trial registrationhttps://doi.org/10.1186/ISRCTN34202533