Dynamic Recruitment of Licensing Factor Cdt1 to Sites of DNA Damage

For genomic integrity to be maintained, the cell cycle and DNA damage responses must be linked. Cdt1, a G1-specific cell-cycle factor, is targeted for proteolysis by the Cul4-Ddb1Cdt2 ubiquitin ligase following DNA damage. Using a laser nanosurgery microscope to generate spatially restricted DNA damage within the living cell nucleus, we show that Cdt1 is recruited onto damaged sites in G1 phase cells, within seconds of DNA damage induction. PCNA, Cdt2, Cul4, DDB1 and p21Cip1 also accumulate rapidly to damaged sites. Cdt1 recruitment is PCNA-dependent, whereas PCNA and Cdt2 recruitment are independent of Cdt1. Fitting of fluorescence recovery after photobleaching profiles to an analytic reaction-diffusion model shows that Cdt1 and p21Cip1 exhibit highly dynamic binding at the site of damage, whereas PCNA appears immobile. Cdt2 exhibits both a rapidly exchanging and an apparently immobile subpopulation. Our data suggest that PCNA provides an immobile binding interface for dynamic Cdt1 interactions at the site of damage, which leads to rapid Cdt1 recruitment to damaged DNA, preceding Cdt1 degradation

Efficiency of a borehole seal by means of pre-compacted bentonite blocks

The backfilling and sealing of shafts and galleries is an essential part of the design of underground repositories for high-level radioactive waste. Part of the EC funded project RESEAL studied the feasibility of sealing off a borehole in plastic Boom Clay by means of pre-compacted bentonite blocks. Two bentonites, namely the FoCa and Serrata clay, have been used. Based on laboratory tests, the bentonite blocks had an initial dry density of about 1.8 g/cm3 to obtain a swelling pressure of about 4.4 MPa, corresponding to the in situ lithostatic stress, at full saturation. The set-up was equipped with several sensors to follow-up the behaviour of the seal and the surrounding host rock during hydration. Full saturation was reached after five months and was mainly reached by natural hydration. Swelling pressure was lower than originally foreseen due to the slow reconsolidation of the host rock. Later on, the efficiency of the seal with respect to water, gas and radionuclide migration was tested. The in situ measured permeability of the seals was about 5 × 10-13 m/s. A gas breakthrough experiment did not show any preferential gas migration through the seal. No evidences of a preferential pathway could be detected from 125I tracer test result

Tailored carrier/bacteria technology for rehabilitation of areas with pesticide-containing pollution – AQUAREHAB WP2

Postprint (published version

Survival of cervical cancer patients at Moi teaching and Referral Hospital, Eldoret in western Kenya

Background Cervical cancer is a major health burden and the second most common cancer after breast cancer among women in Kenya. Worldwide cervical cancer constitutes 3.1% of all cancer cases. Mortality rates are greatest among the low-income countries because of lack of awareness, screening and early-detection programs and adequate treatment facilities. The main aim was to estimate survival and determine survival predictors of women with cervical cancer and limited resources in western Kenya. Methods Retrospective charts review of women diagnosed with cervical cancer and follow-up for two years from the date of the histologic diagnosis. The outcome of interest was death or survival at two years. Kaplan Meier estimates of survival, log-rank test and Cox proportional hazards regression were used in the survival analysis. Results One hundred and sixty-two (162) participants were included in the review. The median duration was 0.8 (interquartile range (IQR) 0.3, 1.6) years. The mean age at diagnosis was 50.6 years (SD12.5). The mean parity was 5.9 (SD 2.6). Fifty percent (50%) did not have health insurance. Twenty six percent (26%) used hormonal contraceptives, 25.9% were HIV positive and 70% of them were on anti-retroviral treatment. The participants were followed up for 152.6 person years. Of the 162 women in the study, 70 (43.2%) died giving an overall incidence rate (IR) of 45.9 deaths per 100 person years of follow up. The hazard ratios were better for the patients who survived (0.44 vs 0.88, p-value \u3c 0.001), those who had medical insurance (0.70 vs 0.48, p-value = 0.007) and those with early stage at diagnosis (0.88 vs 0.39, p-value \u3c 0.001). Participants who were diagnosed at late stage of the disease according to the International Federation of Gynecology and Obstetrics staging for cervical cancer (FIGO stage 2B-4B) had more than eight times increased hazard of death compared to those who were diagnosed at early stage (1-2A): Hazard Ratio: 8.01 (95% CI 3.65, 17.57). Similarly, those who underwent surgical management had 84% reduced hazard of mortality compared to those who were referred for other modes of care: HR: 0.16 (95% CI: 0.07, 0.38). Conclusion: Majority of the participants were diagnosed late after presenting with symptoms. The 1 and 2-year survival probability after diagnosis of cervical cancer was 57% AND 45% respectively. It is imperative that women present early since surgery gives better prognosis or better still screening of all women prioritized

A protocol paper: community engagement interventions for cardiovascular disease prevention in socially disadvantaged populations in the UK: an implementation research study

Background: Cardiovascular disorders (CVD) are the single greatest cause of mortality worldwide. In the UK, the National Health Service (NHS) has launched an initiative of health checks over and above current care to tackle CVD. However, the uptake of Health Checks is poor in disadvantaged communities. This protocol paper sets out a UK-based study (Sussex and Nottingham) aiming to co-produce a community delivered CVD risk assessment and coaching intervention to support community members to reduce their risk of CVD. The overall aim of the project is to implement a tailored-to-context community engagement (CE) intervention on awareness of CVD risks in vulnerable populations in high, middle and low-income countries. The specific objectives of the study are to enhance stakeholder' engagement; to implement lifestyle interventions for cardiovascular primary prevention, in disadvantaged populations and motivate uptake of NHS health checks. Methods: This study uses both qualitative and quantitative methods in three phases of evaluation, including pre-, per-and post-implementation. To ensure contextual appropriateness the 'Scaling-up Packages of Interventions for Cardiovascular disease prevention in selected sites in Europe and Sub-Saharan Africa: An implementation research' (SPICES) project will organize a multi-component community-engagement intervention. For the qualitative component, the pre-implementation phase will involve a contextual assessment and stakeholder mapping, exploring potentials for CVD risk profiling strategies and led by trained Community Health Volunteers (CHV) to identify accessibility and acceptability. The per-implementation phase will involve healthy lifestyle counselling provided by CHVs and evaluation of the outcome to identify fidelity and scalability. The post-implementation phase will involve developing sustainable community-based strategies for CVD risk reduction. All three components will include a process evaluation. A stepped wedge cluster randomised trial of the roll out will focus on implementation outcomes including uptake and engagement and changes in risk profiles. The quantitative component includes pre and post-intervention surveys. The theory of the socio-ecological framework will be applied to analyse the community engagement approach. Discussion: Based on the results ultimately a sustainable community engagement-based strategy for the primary prevention of CVD risk will be developed to enhance the performance of NHS health care in the UK. The Trial Registration number is ISRCTN68334579

Host phenotype characteristics and MC1R in relation to early-onset basal cell carcinoma.

Basal cell carcinoma (BCC) incidence is increasing, particularly among adults under the age of 40 years. Pigment-related characteristics are associated with BCC in older populations, but epidemiologic studies among younger individuals and analyses of phenotype-genotype interactions are limited. We examined self-reported phenotypes and melanocortin 1 receptor gene (MC1R) variants in relation to early-onset BCC. BCC cases (n=377) and controls with benign skin conditions (n=390) under the age of 40 years were identified through Yale's Dermatopathology database. Factors most strongly associated with early-onset BCC were skin reaction to first summer sun for 1 hour (severe sunburn vs. tan odds ratio (OR)=12.27, 95% confidence interval (CI)=4.08-36.94) and skin color (very fair vs. olive OR=11.06, 95% CI=5.90-20.74). Individuals with two or more MC1R non-synonymous variants were 3.59 times (95% CI=2.37-5.43) more likely to have BCC than those without non-synonymous variants. All host characteristics and MC1R were more strongly associated with multiple BCC case status (37% of cases) than a single BCC case status. MC1R, number of moles, skin reaction to first summer sun for 1 hour, and hair and skin color were independently associated with BCC. BCC risk conferred by MC1R tended to be stronger among those with darker pigment phenotypes, traditionally considered to be at low risk of skin cancer

Wake up, wake up! It's me! It's my life! patient narratives on person-centeredness in the integrated care context: a qualitative study

Person-centered care emphasizes a holistic, humanistic approach that puts patients first, at the center of medical care. Person-centeredness is also considered a core element of integrated care. Yet typologies of integrated care mainly describe how patients fit within integrated services, rather than how services fit into the patient's world. Patient-centeredness has been commonly defined through physician's behaviors aimed at delivering patient-centered care. Yet, it is unclear how 'person-centeredness' is realized in integrated care through the patient voice. We aimed to explore patient narratives of person-centeredness in the integrated care context

RESEAL II: a large-scale in situ demonstration for repository sealing in an argillaceous host rock: phase II

Final ReportPreprin

On the determinants of local government debt: Does one size fit all?

This paper analyzes the factors that directly influence levels of debt in Spanish local governments. Specifically, the main objective is to find out the extent to which indebtedness is originated by controllable factors that public managers can influence, or whether it hinges on other variables beyond managers’ control. The importance of this issue has intensified since the start of the crisis in 2007, due to the abrupt decline of revenues and, simultaneously, to the stagnation (or even increase) in the levels of costs facing these institutions face. Results can be explored from multiple perspectives, given that the set of explanatory factors is also multiple. However, the most interesting result relates to the varying effect of each covariate depending on each municipality’s specific debt level, which suggests that economic policy recommendations should not be homogeneous across local governments