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Additional file 1: Table S1. Table displaying optimal cut-offs for the six tumor features determined previously (Walker et al. 2023) in the additive feature combination approach. Table S2. SLS tumors (n=13) that showed discordant MMR IHC findings between clinical diagnostic testing before study entry and testing completed internally during this study and the change in their MMR status and/or pattern of MMR protein loss. Table S3. The concordance between the final MMR IHC result and the predicted dMMR status from the additive feature combination approach overall and by tumor type. Table S4. The tumor MLH1 methylation testing completed for SLS tumors prior to entering the study showing either negative, inconclusive, or not tested results and the subsequent MLH1 methylation testing results from internal testing using MethyLight and MS-HRM assays highlighting the positive MLH1 methylation results found by this study. Table S5. Presentation of germline pathogenic variants and variants of uncertain clinical significance (VUS) identified in the MMR, MUTYH and POLE genes. Table S6. Summary of the clinicopathological features for the double somatic MMR mutation (dMMR-DS) tumors overall and by tumor type. Figure S1. Bar plots presenting the results from the additive tumor feature combination approach to assess the MMR status in the double somatic mutation cohort for A) all tumors combined and separated by B) CRC, C) EC and D) SST tissue types. Figure S2. Bar plot presenting the prevalence of pathogenic/likely pathogenic somatic mutations (including loss of heterozygosity, LOH) by subtype for the study cohort. Figure S3. Pie graphs displaying the frequency of the mutation combination type (two single somatic mutations versus a single somatic mutation with loss of heterozygosity (LOH)) as well as the type of mutation A) overall and B) separated by tissue type. Figure S4. Bar graphs presenting the site distribution in the double somatic mutation cohort across all CRCs and SSTs. Figure S5. Boxplots presenting the site distribution in the double somatic mutation cohort across all A) CRCs and B) SSTs. Significant (< 0.05) p-values are indicated for pairwise (t-test) and multigroup comparisons (Anova). Figure S6. Scatter plots presenting the PREMM5 score distribution in the test cohort for A) all tumors combined and separated by B) CRC, C) EC and D) SST tissue types. Figure S7. The distribution of tumor values for each of the six features that are included in the additive feature combination approach for determining tumor dMMR status grouped by molecular subtype and by combining sporadic dMMR groups dMMR-DS and dMMR-MLH1me into a “sporadic combined” group.

The objective of this scoping review is to identify key characteristics related to the concept of digital identity for children aged 0 to 8 years old on social networking sites.

Summarisation of research results in plain language is crucial for promoting public understanding of research findings. The use of Natural Language Processing to generate lay summaries has the potential to relieve researchers' workload and bridge the gap between science and society. The aim of this narrative literature review is to describe and compare the different text summarisation approaches used to generate lay summaries. We searched the databases Web of Science, Google Scholar, IEEE Xplore, Association for Computing Machinery Digital Library and arXiv for articles published until 6 May 2022. We included original studies on automatic text summarisation methods to generate lay summaries. We screened 82 articles and included eight relevant papers published between 2020 and 2021, all using the same dataset. The results show that transformer-based methods such as Bidirectional Encoder Representations from Transformers (BERT) and Pre-training with Extracted Gap-sentences for Abstractive Summarization (PEGASUS) dominate the landscape of lay text summarisation, with all but one study using these methods. A combination of extractive and abstractive summarisation methods in a hybrid approach was found to be most effective. Furthermore, pre-processing approaches to input text (e.g. applying extractive summarisation) or determining which sections of a text to include, appear critical. Evaluation metrics such as Recall-Oriented Understudy for Gisting Evaluation (ROUGE) were used, which do not consider readability. To conclude, automatic lay text summarisation is under-explored. Future research should consider long document lay text summarisation, including clinical trial reports, and the development of evaluation metrics that consider readability of the lay summary.

"A scoping review to map instruments used to assess distress in T2 diabetes." Screening for distress in people living with diabetes could potentially identify which stressors could be ameliorated by interventions, using valid and reliable measures is important. This review will map and identify the available validated measures of distress used in the field of type 2 diabetes. Using a validated instrument to assess distress is one strategy healthcare providers can use to identify distress in the clinical setting and develop structured plans to address specific needs.

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

Additional file 1: Supplementary Table 1. Female Sub-analysis investigating the association between SPS and characteristics/ lifestyle factors. Supplementary Table 2. Female Sub-analysis investigating the association between WHO criteria I and characteristics/ lifestyle factors. Supplementary Table 3. Female Sub-analysis investigating the association between WHO criteria III and characteristics/ lifestyle factors. Supplementary Table 4. Female Sub-analysis investigating the association between both WHO criteria I and III and characteristics/ lifestyle factors. Supplementary Table 5. Female Sub-analysis investigating the association between CRC and characteristics/ lifestyle factors. Supplementary Table 6. Female Sub-analysis investigating the association between SPS patients with no CRC and characteristics/ lifestyle factors

Additional file 1.

This thesis was scanned from the print manuscript for digital preservation and is copyright the author. Researchers can access this thesis by asking their local university, institution or public library to make a request on their behalf. Monash staff and postgraduate students can use the link in the References field.

Additional file 4. SCRIPT study consent form.

Additional file 2: Supplementary file B. TIDIeR checklist for the intervention.

Additional file 3. Example colorectal cancer risk report and screening recommendations for a participant’s GP at moderate risk in the SCRIPT study.

Additional file 1. Standard cancer risk reduction information provided to control participants in the SCRIPT study.

Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10-8 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30-1.69, p = 8.47 × 10-9) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65-2.77, p = 9.19 × 10-9 and rs144717887, HR = 2.01, 95% CI 1.57-2.58, p = 3.14 × 10-8), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings.

Additional file 2. Example colorectal cancer risk report and screening recommendations for a participant’s GP at moderate risk in the SCRIPT study.

Surface cracks are a very common indicator of potential structural faults. Their early detection and monitoring is an important factor in structural health monitoring. Left untreated, they can grow in size over time and require expensive repairs or maintenance. With recent advances in computer vision and deep learning algorithms, the automatic detection and segmentation of cracks for this monitoring process have become a major topic of interest. This review aims to give researchers an overview of the published work within the field of crack analysis algorithms that make use of deep learning. It outlines the various tasks that are solved through applying computer vision algorithms to surface cracks in a structural health monitoring setting and also provides in-depth reviews of recent fully, semi and unsupervised approaches that perform crack classification, detection, segmentation and quantification. Additionally, this review also highlights popular datasets used for cracks and the metrics that are used to evaluate the performance of those algorithms. Finally, potential research gaps are outlined and further research directions are provided.

Additional file 1: File A. Consent form for general practitioners. File B. Consent form for participants. File C. Baseline questionnaire. File D. Control video. File E. Control email brochure. File F. Teletrial decision aid for email. File G. Video decision aid for males. File H. Video decision aid for females. Files I. 1-month follow up questionnaire. File J. 6-month follow-up questionnaire

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

BackgroundInitiating screening at an earlier age based on cancer family history is one of the primary recommended strategies for the prevention and detection of early-onset colorectal cancer (EOCRC), but data supporting the effectiveness of this approach are limited. The authors assessed the performance of family history-based guidelines for identifying individuals with EOCRC.MethodsThe authors conducted a population-based, case-control study of individuals aged 40 to 49years with (2473 individuals) and without (772 individuals) incident CRC in the Colon Cancer Family Registry from 1998 through 2007. They estimated the sensitivity and specificity of family history-based criteria jointly recommended by the American Cancer Society, the US Multi-Society Task Force on CRC, and the American College of Radiology in 2008 for early screening, and the age at which each participant could have been recommended screening initiation if these criteria had been applied.ResultsFamily history-based early screening criteria were met by approximately 25% of cases (614 of 2473 cases) and 10% of controls (74 of 772 controls), with a sensitivity of 25% and a specificity of 90% for identifying EOCRC cases aged 40 to 49years. Among 614 individuals meeting early screening criteria, 98.4% could have been recommended screening initiation at an age younger than the observed age of diagnosis.ConclusionsOf CRC cases aged 40 to 49years, 1 in 4 met family history-based early screening criteria, and nearly all cases who met these criteria could have had CRC diagnosed earlier (or possibly even prevented) if earlier screening had been implemented as per family history-based guidelines. Additional strategies are needed to improve the detection and prevention of EOCRC for individuals not meeting family history criteria for early screening.

Additional file 1 Supplementary tables 1–6, supplementary figures 1–3, supplementary text 1. Suppl. table 1 - Summary statistics for the genetic association with bilirubin levels, and sex-stratified colorectal cancer risk. Suppl. table 2 - Participating studies in the genetic consortia (GECCO/ CCFR/ and CORECT). Suppl. table 3 - Associations between unconjugated bilirubin (UCB) levels and colorectal cancer risk after different sensitivity analyses in the EPIC study. Suppl. table 4 - Results for the Mendelian randomization sensitivity analyses. Suppl. table 5 - Results for the Mendelian randomization sensitivity analyses: positive control outcomes for pancreatic cancer. Suppl. table 6 - Results for genome-wide associations of instruments with other phenotypes. Suppl. figure 1 - Cubic spline modeling of unconjugated bilirubin (UCB) levels in relation to colorectal cancer risk in the EPIC study. Suppl. figure 2 - Association between UGT1A1 polymorphism (rs6431625) and unconjugated bilirubin (UCB) levels in the EPIC study (with available GWAS data). Suppl. figure 3 - Directed acyclic graph (DAG) of the causal structure of associations between unconjugated bilirubin (UCB) levels in relation to colorectal cancer risk in the EPIC study. Suppl. text 1 - Specific funding sources and acknowledgements of participating studies.

We perform extensive analysis of graphene Josephson junctions embedded in microwave circuits. By comparing a diffusive junction at 15 mK with a ballistic one at 15 mK and 1 K, we are able to reconstruct the current-phase relation.

Family history of colorectal cancer is a well-established and consistently strong risk factor for this disease. However, simply counting the number of affected relatives is an imprecise measure of colorectal cancer risk. We have reviewed current colorectal cancer screening guidelines from Australia, New Zealand, Canada, the US, and UK, and found that all, including the Australian National Health and Medical Research Council 2005 guidelines, assign people to risk categories largely based on age and rudimentary metrics of family history and recommend screening regimens. We claim that these guidelines are not sufficiently precise for a large proportion of people within these categories, as there is a substantial variation in colorectal cancer risk, even for people with the same family history, and even for people with a predisposing mutation in the same gene, or set of genes. If there was a tool to estimate individual colorectal cancer risk based on all known risk factors for the disease - personal and family history of cancer (including ages, ages at diagnoses, and genetic relationships across multiple generations), all known genetic factors (rare high-risk genetic mutations as well as common genetic variants), environmental factors and personal characteristics - then accurate prediction of future risk of colorectal cancer (personalised risk) may be possible. The development and utility of such a comprehensive risk prediction tool is important for appropriate personalised clinical management, including targeted colorectal cancer screening.

BackgroundPrevious genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.MethodsWe conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.ResultsThe discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.ConclusionsThis study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

APS March Meeting, Boston, MA, March 4-8, 2019. -- https://www.aps.org/meetings/meeting.cfm?name=MAR19, Funds were provided by the Spanish MINECO (grants MAT2015-68204-R and Excellence Unit Maria de Maeztu MDM-2015- 0538) and the European Union (COST 15128 Molecular Spintronics and QUANTERA SUMO projects)

Resumen del trabajo presentado al 14th International Workshop on Magnetism & Superconductivity at the Nanoscale, celebrado en Coma-Ruga, El Vendrell (España) del 1 al 6 de julio de 2018., Superradiance is a coherent enhanced emission of electromagnetic radiation by an ensemble of identical atoms. The light-matter interaction introduces long-range correlations and gives rise to collective atomic states that are the ones that (super)radiate. Correlations can also arise from intrinsic interactions between the atomic degrees of freedom. In spite of the central role that light-matter hybridization plays in quantum optics and quantum computation, the competition of these two effects remains relatively unexplored. Here, we study the interaction of microwave radiation propagating via a superconducting co-planar transmission wave guide with model spin-1/2 DPPH molecules that interact weakly with each other along one-dimensional chains. The range of intrinsic magnetic correlations is controlled by changing either magnetic field (0< μ0H < 1 T) or temperature (170 mK < T < 4.2 K). We find that the onset of such correlations below 1 K suppresses the superradiant emission that is observed in the uncorrelated paramagnetic state. These results allow exploring new states of matter, arising from the interplay between magnetic and light-matter couplings, and provide a tool to externally control superradiance.

Table S1. For interval and screen-detected invasive breast cancer, marginal risk estimates for Cumulus, Altocumulus and Cirrocumulus measures of dense area and percent density adjusted for age and BMI. Table S2. For interval and screen-detected invasive breast cancer, multivariable risk estimates for Cumulus, Altocumulus and Cirrocumulus measures of dense area and percent density adjusted for age and BMI. Table S3. Combined (all breast cancer); total (summary of interval and screen-detected); and -2Î of log likelihood (LL) for Cumulus, Altocumulus and Cirrocumulus measures of dense area and percent density adjusted for age and BMI and P value for the differences. (DOCX 36 kb)

Growing evidence from both epidemiology and basic science suggest an inverse association between Alzheimer’s disease (AD) and cancer. We examined the genetic relationship between AD and various cancer types using GWAS summary statistics from the IGAP and GAME-ON consortia. Sample size ranged from 9931 to 54,162; SNPs were imputed to the 1000 Genomes European panel. Our results based on cross-trait LD Score regression showed a significant positive genetic correlation between AD and five cancers combined (colon, breast, prostate, ovarian, lung; r g = 0.17, P = 0.04), and specifically with breast cancer (ER-negative and overall; r g = 0.21 and 0.18, P = 0.035 and 0.034) and lung cancer (adenocarcinoma, squamous cell carcinoma and overall; r g = 0.31, 0.38 and 0.30, P = 0.029, 0.016, and 0.006). Estimating the genetic correlation in specific functional categories revealed mixed positive and negative signals, notably stronger at annotations associated with increased enhancer activity. This suggests a role of gene expression regulators in the shared genetic etiology between AD and cancer, and that some shared variants modulate disease risk concordantly while others have effects in opposite directions. Due to power issues, we did not detect cross-phenotype associations at individual SNPs. This genetic overlap is not likely driven by a handful of major loci. Our study is the first to examine the co-heritability of AD and cancer leveraging large-scale GWAS results. The functional categories highlighted in this study need further investigation to illustrate the details of the genetic sharing and to bridge between different levels of associations.

Trabajo presentado a la XXXVI Reunión Bienal de la Real Sociedad Española de Física, celebrada en Santiago de Compostela del 17 al 21 de julio de 2017.

Resumen del trabajo presentado a la XXXVI Reunión Bienal de la Real Sociedad Española de Física, celebrada en Santiago de Compostela del 17 al 21 de julio de 2017., The practical realization of quantum computation schemes faces the challenge of increasing the number of qubits while keeping errors below a threshold that allows their coherent manipulation. This dilemma is of particular relevance for proposals involving electron spins. The implementation of even the simplest quantum algorithm implies coupling two or more of such qubits in a controlled manner. However, dipolar interactions between them are also an important source of decoherence, which has severely limited progressing beyond the realization of elemental two-qubit gates. Here, we explore a way to scale up quantum resources, without introducing additional decoherence, by integrating several electron spin qubits in a single magnetic ion with spin S > ½. This approach is illustrated with a Gd3+ ion trapped inside a suitably chosen polyoxoanion [Gd(H2O)P5W30O110]12- (GdW30, Fig 1). Electron paramagnetic resonance experiments (Fig. 1) have been performed on quasi-independent molecules diluted in a crystal of the diamagnetic isostructural derivative [Y(H2O)P5W30O110]12-. The full energy-level spectrum and the orientations of the magnetic anisotropy axes have been determined by means of continuouswave electron paramagnetic resonance experiments, using X-band (9–10 GHz) cavities and on-chip superconducting waveguides (0.1-14 GHz) and 1.5-GHz resonators. The results show that seven allowed transitions between the 2S + 1 spin states can be separately addressed. Spin coherence 1/T2 and spin-lattice relaxation 1/T1 rates have been measured for each of these transitions in properly oriented single crystals. The results suggest that quantum spin coherence is limited by residual dipolar interactions with neighbor electronic spins. Coherent Rabi oscillations have been observed for all transitions. The Rabi frequencies increase with microwave power and agree quantitatively with predictions based on the spin Hamiltonian of the molecular spin. We argue that the spin states of each Gd3+ ion can be mapped onto the states of three addressable qubits (or, alternatively, of a d = 8-level “qudit”), for which the seven allowed transitions form a universal set of operations. Within this scheme, one of the coherent oscillations observed experimentally provides an implementation of a controlled-controlled-NOT (or Toffoli) three-qubit gate. Our findings open prospects for developing more complex and robust quantum computation schemes based on spin qubits., Funds were provided by the Spanish MINECO (Grants No. MAT2015-68204-R, No. CTQ2015-64486-R, No. MAT-2014-56143-R, No. CTQ2014-52758-P, and No. FIS2015-70856-P and Excellence Unit María de Maeztu MDM-2015-0538), the European Union (ERC Grants No. SPINMOL and DECRESIM and COST 15128 Molecular Spintronics project), the Gobierno de Aragón (Grants No. E98-MOLCHIP and No. E33), Comunidad de Madrid (Research Network QUITEMAD+), and the Generalidad Valenciana (Prometeo and ISIC-Nano Programs of Excellence). A.G.-A. thanks MINECO for a Ramón y Cajal Fellowship.

Annual incidence rates (AIR) and 95% confidence intervals for colorectal cancer and extra-colonic cancer. (DOCX 15 kb)

We show that several qubits can be integrated in a single magnetic ion, using its internal electronic spin states with energies tuned by a suitably chosen molecular environment. This approach is illustrated with a nearly-isotropic Gd(III) ion entrapped in a polyoxometalate molecule. Experiments with microwave technologies, either three dimensional cavities or quantum superconducting circuits, show that this magnetic molecule possesses the number of spin states and the set of coherently addressable transitions connecting these states that are needed to perform a universal three-qubit processor or, equivalently, a d=8-level 'qudit'. Our findings open prospects for developing more sophisticated magnetic molecules which can result in more powerful and noise resilient quantum computation schemes., Comment: 5 pages, 4 figures

High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.

Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E-05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89-0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn's-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn's-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P

Memoria de Tesis Doctoral presentada por Mark David Jenkins Sánchez, realizada bajo la dirección del Dr. Fernando Luis Vitalla en el Departamento de Física de la Materia Condensada y en Instituto de Ciencia de Materiales de Aragón (Universidad de Zaragoza –CSIC)., Uno de los retos actuales en el campo de la información es la construcción de un ordenador cuántico. En un ordenador cuántico se sustituye la unidad de información de los ordenadores clásicos, el bit, por un bit cuántico o qubit. El principio de superposición, inherente a la física cuántica, permite entonces manejar estados >superposición>. Esta posibilidad abre una puerta a la implementación de nuevos algoritmos y podría permitir simulaciones y cálculos inpracticables con tecnologías clásicas. Los tres obstáculos principales a la hora de construir un ordenador cuántico son: - Encontrar sistemas físicos que tengan las propiedades adecuadas para ser qubits. Se buscan principalmente que sean equivalentes a un sistema cuántico de dos niveles en el régimen de trabajo. Existen sistemas que, de forma natural, ya presentan esta característica, por ejemplo espines nucleares, atomicos o moleculares o dipolos eléctricos. Por otro lado, también existen sistemas sintéticos que pueden fabricarse con las características deseadas. Estos últimos son determinados circuitos cuánticos como los qubits de carga o qubits de flujo (superconductores). - Encontrar sistemas para inicializar, leer, escribir y manipular los qubits así como para acoplarlos entre sí generando entrelazamiento cuántico y creando puertas lógicas cuánticas. Los qubits no solo tienen que almacenar información, sino que además deben poder ser manipulados de forma efectiva. Asimismo, la información ha de ser transferida de un lugar del sistema a otro (bus cuántico). La forma más natural de manipular los distintos qubits es mediante su acoplo a radiación electromagnética. Los fotones son de forma natural objetos cuánticos y ofrecen un muy efectivo medio para la transfencia de información cuántica. - Mantener la coherencia cuántica de los qubits. Los sistemas y efectos cúanticos son típicamente muy sensibles a perturbaciones externas y cualquier interacción con el entorno puede destruir su coherencia. La necesidad de aislarlos adecuadamente del entorno compite directamente con la facilidad de manipularlos y ponerlos en interacción mutua. En este contexto, tiene especial importancia el estudio de la interacción de fotones individuales con sistemas cuánticos candidatos a ser qubits. El ejemplo arquetípico para el estudio de esta interacción son los sistemas de electrodinámica cúantica de cavidades (Cavity Quantum Electrodynamics o CQED en inglés). Éstos consisten en un sistema cuántico de dos niveles acoplado a único modo de la radiación electromagnética, por ejemplo, a fotones almacenados en una cavidad. La intensidad del acoplo fotón-qubit ha de superar las frequencias de decoherencia ambos subsistemas. Este régimen de acoplo fuerte permite que, durante el tiempo de vida del sistema, se pueda realizar un numero suficientemente elevado de operaciones. Con el objeto de aumentar el acoplo entre los fotones de una cavidad y un qubit, se han investigado distintos tipos de cavidades y qubits que permiten alcanzar el régimen de acoplo fuerte. Uno de los más interesantes es lo que ahora se conoce como electrodinámica cuántica de circuitos (Circuit QED), que consiste en usar tecnologías de circuitos integrados y superconductores para fabricar cavidades y qubits adaptados para aplicaciones en el procesado cuántico de información. Uno de los sistemas más utilizados en Circuit QED es el qubit de carga (Cooper pair box) acoplado a través de la componente eléctrica del campo a un resonador coplanar superconductor (superconducting coplanar waveguide resonator). La geometría de una guía de ondas coplanar permite aumentar la densidad de energía electromagnética (y por consiguiente el acoplo) con respecto a una cavidad tridimensional estándar. Este sistema presenta acoplo, fuerte y permite la realización de operaciones sobre el qubit e incluso entrelazar múltiples qubits acoplados a la misma cavidad. Sistemas candidatos a qubits que se acoplan al campo magnético, como por ejemplo sistemas de espines de estado sólido, tambien son interesantes por sus posibles aplicaciones para el almacenamiento de información cuántica y para proporcionar una interconexión entre fotones de radio-frecuencias con fotones ópticos. Experimentos realizados en los últimos años demuestran la posibilidad de acoplar coherentemente centros NV y P1 de diamante con circuitos cúanticos como resonadores superconductores o qubits de flujo. Estos defectos en diamante actuan como sistemas de espin 1 y se acoplan colectivamente al circuito proporcionando un aumento en el acoplo proporcional a la raiz cuadrada de número de espines. El acoplo fuerte se consigue gracias a este factor junto con la alta coherencia de los centros magnéticos (tiempos de coherencia de 1-2 ms a temperatura ambiente). También se ha demostrado acoplo fuerte magnético, incluso a temperatura ambiente, entre radicales paramagnéticos de spin 1/2 y cavidades de microondas tridimensionales. El uso qubits de espin abre también la posibilidad a otros sistemas algo más complejos. Los >single molecule magnets> (moleculas iman ó SMMs) son moléculas organometalicas formadas por un núcleo de alto espín rodeado de ligandos orgánicos que, de forma natural, se organizan en cristales moleculares. El alto valor de su espín puede permitir que el régimen de acoplo fuerte sea más fácil de alcanzar y podría llevar a su aplicación como memorias cuánticas. Los SMMs son también iteresantes por que permiten manipular químicamente sus propiedades para distintas aplicaciones. Si nos restringimos solo al campo de la información cuántica, estos sistemas pueden actuar no sólo como qubits individuales sino que se pueden diseñar para que una única molécula contenga múltiples qubits débil o fuertemente entrelazados, para actuar como puertas lógicas o como simuladores cuánticos. Muchas de las aplicaciones de SMMs más sofisticados requieren acoplar moléculas individuales al campo magnético de un resonador, un reto aún más complicado que el acoplo a cristales macroscópicos. Si este límite fuera alcanzable, se podrían utilizar circuitos supercondutores para manipular y transferir coherentemente información entre qubits de espin, proporcionando una arquitectura adecuada para implementar un procesador cuántico de spines. Si nos inspiramos en los sistemas de Circuit QED, podemos imaginar construir un sistema similar donde se colocarían moléculas individuales en las posiciones de la cavidad donde haya máximo campo magnético para el modo deseado de las microondas. Los espines podrían entonces sintonizarse individualmente utilizando campos magnéticos locales para ponerlos en resonancia con la cavidad e intercambiarían información. El principal objetivo en esta tesis, es comprobar la viabilidad de propuestas como esta y dar los primeros pasos hacia su realización. Los acoplos alcanzables en la actualidad para espines individuales son todavía demasiado bajos como para superar sus los límites inmpuestos por sus tiempos de coherencia. Esto nos deja con dos, alternativas para mejorar el acoplo: - Encontrar sistemas de espín con mejores propiedades (tanto acoplo más fuerte como mejor coherencia) - Modificar las cavidades para aumentar el campo magnético y, por tanto, el acoplo. Teniendo esto en cuenta, los objetivos concretos de la tesis son: - Establecer que características deben tener los sistemas de espín para acoplarse fuertemente con un circuito cuántico - Estudiar las propiedades de diferentes familias de SMMs y ver si cumplen con las condiciones requeridas para el acoplo fuerte, tento en forma de cristales moleculares como de moléculas individuales. - Diseñar nuevos resonadores de Circuit QED para concentrar el campo de microondas en regiones, optimizando así la interacción con pequeños grupos de espines o moléculas magnéticas. Explorar también si estas modificaciones cambian de forma sustancial las propiedades básicas del resonador.

Hip fractures are a common type of fragility fracture that afflict 293,000 Americans (over 5,000 per week) and 35,000 Canadians (over 670 per week) annually. Despite the large population impact the optimal fixation technique for low energy femoral neck fractures remains controversial. The primary objective of the FAITH study is to assess the impact of cancellous screw fixation versus sliding hip screws on rates of revision surgery at 24 months in individuals with femoral neck fractures. The secondary objective is to determine the impact on health-related quality of life, functional outcomes, health state utilities, fracture healing, mortality and fracture-related adverse events. FAITH is a multi-centre, multi-national randomized controlled trial utilizing minimization to determine patient allocation. Surgeons in North America, Europe, Australia, and Asia will recruit a total of at least 1,000 patients with low-energy femoral neck fractures. Using central randomization, patients will be allocated to receive surgical treatment with cancellous screws or a sliding hip screw. Patient outcomes will be assessed at one week (baseline), 10 weeks, 6, 12, 18, and 24 months post initial fixation. We will independently adjudicate revision surgery and complications within 24 months of the initial fixation. Outcome analysis will be performed using a Cox proportional hazards model and likelihood ratio test. This study represents major international efforts to definitively resolve the treatment of low-energy femoral neck fractures. This trial will not only change current Orthopaedic practice, but will also set a benchmark for the conduct of future Orthopaedic trials. The FAITH trial is registered at ClinicalTrials.gov (Identifier NCT00761813 ).

Background & aimsHeritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.MethodsWe conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.ResultsBased on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)).ConclusionsIn a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10−10) and BMP2 (rs4813802, P = 4.65×10−11). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10−8) and rs11632715 (P = 2.30×10−10). As low-penetrance predisposition variants become harder to identify—owing to small effect sizes and/or low risk allele frequencies—approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases., Author Summary Genome-wide association studies (GWAS) have identified several colorectal cancer (CRC) susceptibility polymorphisms near genes that encode proteins in the bone morphogenetic protein (BMP) pathway. However, most of the inherited susceptibility to CRC remains unexplained. We investigated three of the best candidate BMP genes (GREM1, BMP4, and BMP2) for additional polymorphisms associated with CRC. By extensive validation of polymorphisms with only modest evidence of association in the initial phases of the GWAS, we identified new, independent CRC predisposition polymorphisms close to BMP4 (rs1957636) and BMP2 (rs4813802). Near GREM1, we used additional genotyping around the GWAS-identified polymorphism rs4779584 to demonstrate two independent signals represented by rs16969681 and rs11632715. Common genes with modest effects on disease risk are becoming harder to identify, and approaches based on informed candidate gene selection may become increasingly attractive. In addition, genetic fine mapping around polymorphisms identified in GWAS can deconvolute associations which have arisen owing to two independent functional variants. These types of study can identify some of the apparently missing heritability of common disease.

This paper considers the interplay between technological discontinuities and competitive performance. Much of the work on technological discontinuities has focused on macro levels of analysis such as industries and technologies rather than specific firms. This study uses a historical perspective on Formula 1 motor racing to explore the dynamics between firm level performance and technological discontinuities over a 57 year period. The study supports the findings of previous research that incumbent firms are often unable to adapt to the impact of exogenous shocks. However the study also reveals situations where a relatively small number of firms are able to sustain their competitive superiority through a number of successive discontinuities. I suggest that, in addition to dynamic capabilities, these firms possess sustaining capabilities – munificent resource configurations which extend the time available for firms to adapt to technological changes – thereby allowing them to remain competitive across discontinuities.

An important development in the study of multinational firms and knowledge-based competitive advantage in recent years is the recognition that unique, rent-generating knowledge can be found in many locations around the globe., We consider the dynamics of knowledge-based sources of advantage as they move between geographical locations and multinational and other firm level networks using the specialist context of Formula 1 motor over a fifty nine year period. We suggest that shifts in competitive advantage are underpinned by the movement of both architectural and component knowledge at both the firm and cluster level, and in particular we suggest that isolated firms can both benefit from and add to cluster level knowledge. We conclude by suggesting ways in which MNEs can adapt their approach to both location and knowledge development in order to enhance their ability to create competitive advantage.

We report on our study of the LFV processes \mu \to e\gamma, \mu\to eee and \mu \to e conversion in the context of Little Higgs models. Specifically we examine the Littlest Higgs with T-parity (LHT) and the Simplest Little Higgs (SLH) as examples of a Product group and Simple group Little Higgs models respectively. The necessary Feynman rules for both models are obtained in the 't Hooft Feynman Gauge up to order v^2/f^2 and predictions for the branching ratios and conversion rates of the LFV processes are calculated to leading order (one-loop level). Comparison with current experimental constraints show that there is some tension and, in order to be within the limits, one requires a higher breaking scale f, alignment of the heavy and light lepton sectors or almost degenerate heavy lepton masses. These constraints are more demanding in the SLH than in the LHT case., Comment: 6 pages, 3 figures, to appear in Proceedings of the XXXIII Intl. Conf. of Theoretical Physics, "Matter to the Deepest", Ustron, Poland, September 11-16, 2009; v2: comments and references added

Contains fulltext : 138857.pdf (Publisher’s version ) (Closed access) The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

School of Management

Background: The Colorectal Cancer Family Registry (Colon CFR) has served as an international resource for studies of the genetics and epidemiology of colorectal cancer (CRC) since 1997. It is the largest family-based resource in the world for the study of CRC and other cancers, such as endometrial cancer, that occur in CRC families. The Colon CFR has recruited participants via six institutions: Cancer Care Ontario, Fred Hutchinson Cancer Research Center, Mayo Clinic, University of Hawaii, University of Southern California Consortium, and University of Melbourne. Methods: CRC cases were recruited from both population-based cancer registries and family cancer clinics. Controls were recruited from population-based sources. Relatives were recruited via cases and controls. Participants were asked to: donate a blood sample; give permission to access any tumor tissue; complete a detailed personal and family history of cancer including degree of relationship, site of cancer and age of diagnosis; and complete a detailed baseline lifestyle questionnaire that was administered across all recruitment sites, which included items on established and suspected risk factors for colorectal cancer: personal characteristics including age, sex, height and weight, country of birth, ethnicity, race and religion; history of exercise, alcohol consumption and smoking; medication use including NSAIDs, cholesterol-lowering agents, diabetes medication and post- menopausal hormone use; history of colorectal cancer screening including fecal occult blood test, sigmoidoscopy, colonoscopy; personal history of surgery including polypectomy, other bowel surgery and hysterectomy; frequency of meat consumption and method of cooking; reproductive history (for women). Participants were also asked for detail information on the frequency of food consumption and portion size using a food frequency questionnaire. Follow-up of participants has been conducted every five years, by questionnaire, to update vital status, surgery, cancer screening, polypectomy, and personal and family history of cancer history. Participants have been characterized for major known predisposing CRC gene mutations and have undergone a genome-wide SNP testing and tested for known CRC SNPs. Results: The Colon CFR has enrolled 35,297 participants (11,635 affected with CRC, 3,629 affected with other cancers, and 20,033 unaffected) who have completed baseline questionnaires. We have 5-year follow-up data on 24,692 participants (6,329 affected with CRC, 2,261 affected with other cancers, and 16,102 unaffected) and 10-year follow-up data on 10,467 (3,654 affected with CRC, 1,182 affected with other cancers, and 5,631 unaffected). We have GWAS data on 3,830 participants, candidate SNP data on 18,000 participants, and mismatch repair gene mutation data on 2,697 participants (and observed 1,697 carriers with a deleterious mutation). Conclusion: This largest and best characterized CRC cohort in the world will facilitate post-GWAS research to provide insight into the role of environmental factors, and how they interact with genetic factors on CRC risk. Researchers are encouraged by the National Cancer Institute (USA) and the Colon CFR investigators to apply for access to this unique resource of data and biospecimens for collaborative research. Citation Format: Aung Ko Win, Daniel D. Buchanan, Noralane M. Lindor, Robert W. Haile, Polly A. Newcomb, Loic Le Marchand, Steven Gallinger, Hopper L. John, Casey Graham, Mark A. Jenkins. The Colon Cancer Family Registry: A major resource for post-GWAS gene-environment studies. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 43.

School of Management

School of Management

School of Management

Coccidiosis, ubiquitous diseases of poultry, seriously impair the growth and feed utilization of livestock and poultry. Coccidiosis causes over $600 million annual losses world-wide and no vaccine is currently available. The goal of this study was to investigate the cellular and molecular mechanisms controlling protective immune responses to coccidia parasites in order to develop immunological control strategy against coccidiosis. The major findings of this study were: 1) cell-mediated immunity plays a major role in protection against coccidiosis, 2) when different genetic lines showing different levels of disease susceptibility were compared, higher T-cell response was seen in the strains of chickens showing higher disease resistance, 3) early interferon secretion was observed in more coccidia-resistant chicken strains, 4) both sporozoite and merozoite antigens were able to induce interferon production, and 5) chicken monoclonal antibodies which detect immunogenic coccidia proteins have been developed. This study provided a good background work for future studies toward the development of recombinant coccidial vaccine. Availability of chicken monoclonal antibodies which detect immunogenic coccidia proteins will enhance our ability to identify potential coccidial vaccine antigens.