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Pathology of tumors associated with pathogenic germline variants in nine breast cancer susceptibility genes
No full textImportance: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contribution to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction.Objective: To characterize tumors associated with BC susceptibility genes in large scale population- or hospital-based studies.Design: Case-control; BRIDGES studySetting: Multicenter, internationalParticipants: 42,680 cases and 46,387 controls, women aged 18-79 years, sampled independently of family history, from 38 studies.Exposures: Protein truncating variants (PTVs) and likely pathogenic missense variants (MSVs) in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.Main Outcomes and Measures: BC ‘intrinsic-like’ subtypes as defined by ER, PR, HER2 status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying PTVs and pathogenic MSVs in the nine BC susceptibility genes.Results: Mean ages at interview (controls) and diagnosis (cases) were 55.1 and 55.8 years respectively. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D and BARD1 variants were associated mainly with triple-negative disease: OR=6.19(95%CI:3.17-12.12), OR=6.19(95%CI:2.99-12.79) and OR=10.05(95%CI:5.27-19.19), respectively. CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+HER2─highgrade subtype (OR=4.99, 95%CI:3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but ORs varied widely, being highest for triple-negative disease (OR=55.32, 95%CI:40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+HER2+, and HR─HER2+subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes a decline in OR was observed with increasing age. Together the nine genes contributed to 27.3% of all triple-negative tumors in women age 40 years. Conclusions and Relevance: Variants in the nine BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies
Polygenic Risk Modelling for Prediction of Epithelial Ovarian Cancer Risk
No full textPolygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28–1.48,AUC:0.588) per unit standard deviation, in women of European ancestries; 1.14(95%CI:1.08–1.19,AUC:0.538) in women of East Asian ancestries; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestries; hazard ratios of 1.36(95%CI:1.29–1.43,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.49(95%CI:1.35-1.64,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs
Multispectral graphene-based electro-optical surfaces with reversible tunability from visible to microwave wavelengths
No full textOptical materials with colour changing abilities have been explored for use in display devices 1, smart windows 2,3 or in the modulation of visual appearance 4–6. The efficiency of these materials, however, has strong wavelength dependence, which limits their functionality to a specific spectral range. Here, we report graphene-based electro-optical devices with unprecedented optical tunability covering the entire electromagnetic spectrum from the visible to microwave. We achieve this non-volatile and reversible tunability by electro-intercalation of lithium into graphene layers in an optically accessible device structure. The unique colour changing capability, together with area-selective intercalation, inspires the fabrication of new multispectral devices, including display devices and electro-optical camouflage coating. We anticipate that these results provide realistic approaches for programmable smart optical surfaces with a potential utility in many scientific and engineering fields such as active plasmonics and adaptive thermal management. </p
European-wide policymaking at the urban level: A qualitative study
No full textBackgroundInter-urban area (UA) health inequalities can be as dramatic as those between high and low-income countries. Policies need to focus on the determinants of health specific to UAs to effect change. This study therefore aimed to determine the degree to which policymakers from different countries could make autonomous health and wellbeing policy decisions for their urban jurisdiction area. MethodsWe conducted a cross-sectional, qualitative interview study with policymakers recruited from 8 European countries (N=37). ResultsThe reported autonomy among policymakers varied considerably between countries, from little or no autonomy and strict adherence to national directives (e.g. Slovak Republic) to a high degree of autonomy and ability to interpret national guidelines to local context (e.g. Norway). The main perceived barriers to implementation of local policies were political, and the importance of regular and effective communication with stakeholders, especially politicians, was emphasised. Having qualified health professionals in positions of influence within the UA was cited as a strong driver of the public health agenda at the UA level. ConclusionLocal-level policy development and implementation depends strongly on the degree of autonomy and independence of policymakers, which in turn depends on the organisation, structure and financial budget allocation of public health services. While high levels of centralisation in small, relatively homogenous countries may enhance efficient use of resources, larger, more diverse countries may benefit from devolution to smaller geographical regions. <br/
Variation in the Risk of Colorectal Cancer for Lynch Syndrome: A retrospective family cohort study A retrospective family cohort study
No full textChemotherapy for Advanced Gallbladder Cancer (GBC): A Systematic Review and Meta-Analysis
No full textBackground: The benefit from chemotherapy, specifically for patients with gallbladder cancer (GBC), has been poorly explored since GBC is mostly studied jointly with other biliary tract cancers (BTC). Methods: Eligible studies reporting outcome of palliative systemic chemotherapy for advanced GBC were identified through MEDLINE, cross-referencing and conferences (PROSPERO-CRD42019155745). Meta-analysis of proportions and calculation of pooled weighted means were performed. Results: 58 eligible studies (n=1,986 patients); cisplatin/gemcitabine (33% of patients), gemcitabine/oxaliplatin (14%) or gemcitabine monotherapy (9%). Estimated pooled overall radiological response rate(ORR), and pooled weighted mean progression-free (PFS) and overall survivals (OS) were 23.2% (95%-CI 20.0-26.5) (I2: 52.5% (p<0.001)), 4.8 months (95%-CI 4.3-5.2) and 8.3 months (95%CI 7.6-8.9), respectively. Patients with non-GBC BTCs achieved a lower ORR than GBC [odds ratio 0.65 (95% CI, 0.50-0.84)]. Conclusions: GBC benefit from chemotherapy differs from other BTCs, with shorter PFS/OS despite higher ORR; new treatment options are urgently required for management of advanced GBC
Managing a Global Retail Brand Across Different Markets:Meta-Analyses of Customers' Responses to Service Encounters
No full textThis study investigates how retailers can leverage their brand to shape customers’ satisfaction with service encounters. It develops and tests hypotheses about how brand, store, and consumer factors moderate customer responses to experience clues during retail service encounters. Six meta-regression analyses synthesize and compare results from 842 satisfaction equations describing customers’ encounters with a global retailer operating 400 stores in 32 countries. The results show how customers weigh their perceptions of service encounters differently depending on brand, store, and consumer factors. In markets where customers believe the retailer has high holistic brand quality, they place less weight on experience clues within the store. In markets where customers believe the retailer’s service brand promise, they place more weight on in-store experience clues. In markets where the retailer promises utilitarian value, customers weigh functional experience clues more heavily. In markets with an online purchasing channel, the effect of experience clues common to offline and online store environments is magnified, and unique clues are diminished. In addition, customers heavily weigh experience clues that fit their goals. In general, retail success factors include high brand quality (which makes customers more forgiving), a service brand promise that is mirrored in the store image (which makes customers attend to the experience clues aligned with them), and the careful monitoring and managing of retail touchpoints (to customize experience clues to each market). In this way, retailers can use customer-based strategies to effectively design and manage their global retail brand in different markets
Disrupting transitions: qualitatively modelling the impact of Covid-19 on UK food and mobility provision
No full textThe 2020 Covid-19 pandemic provides an empirical testing ground for assessing the impact of critical events on societal transitions. Such events are typically seen as exogenous to the transition process, an assumption which is investigated in this paper. Using a qualitative system dynamics modelling approach we conceptualize transition pathways as sets of interacting sequences of events. This enables the analysis of event sequences that constitute the evolving pandemic as impacting on those pathways. We apply this approach to the provision of (auto)mobility and food in the UK. This shows the way in which the pandemic has had a differential effect on ongoing transitions in both systems, sometimes slowing them down, and sometimes accelerating them. In addition, it reveals how it has established new transition pathways. The empirical work further shows how qualitative modelling with system dynamics facilitates an explicit a systematic comparative analysis of transition case studies
Ceramic buckling for determining the residual stress in thin films
No full textA new technique for determination of residual stress in thin films and coatings has been presented. The method consists of focused ion beam milling to create a lamella of thin film, followed by analysis of stress driven buckling profile of undercut lamella (beam) to extract residual stress. The residual stresses in crystalline TiN and Al2O3 films, produced by reactive magnetron sputtering and thermal oxidation, respectively, have been successfully determined by this new technique and validated by conventional X-ray diffraction and photoluminescence piezospectroscopy techniques, respectively. This new technique successfully measures and tracks the evolution of residual stress in as-deposited and different thermally cycled amorphous SiAlN films induced by thermal mismatch or relieved via mechanical twinning in interlayer, where diffraction methods are not applicable, thereby evaluating the thermal cycling performance of amorphous SiAlN coatings for protection of Ti at high temperature
