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Background: Paediatric mortality rates in the United Kingdom are amongst the highest in Europe. Clinically missed deterioration is a contributory factor. Evidence to support any single intervention to address this problem is limited, but a cumulative body of research highlights the need for a systems approach.Methods: An evidence-based, theoretically informed, paediatric early warning system improvement programme (PUMA Programme) was developed and implemented in two general hospitals (no onsite Paediatric Intensive Care Unit) and two tertiary hospitals (with onsite Paediatric Intensive Care Unit) in the United Kingdom. Designed to harness local expertise to implement contextually appropriate improvement initiatives, the PUMA Programme includes a propositional model of a paediatric early warning system, system assessment tools, guidance to support improvement initiatives and structured facilitation and support. Each hospital was evaluated using interrupted time series and qualitative case studies. The primary quantitative outcome was a composite metric (adverse events), representing the number of children monthly that experienced one of the following: mortality, cardiac arrest, respiratory arrest, unplanned admission to Paediatric Intensive Care Unit, or unplanned admission to Higher Dependency Unit. System changes were assessed qualitatively through observations of clinical practice and interviews with staff and parents. A qualitative evaluation of implementation processes was undertaken.Results: All sites assessed their paediatric early warning systems and identified areas for improvement. All made contextually appropriate system changes, despite implementation challenges. There was a decline in the adverse event rate trend in three sites; in one site where system wide changes were organisationally supported, the decline was significant (ß = -0.09 (95% CI: - 0.15, - 0.05); p = < 0.001). Changes in trends coincided with implementation of site-specific changes.Conclusions: System level change to improve paediatric early warning systems can bring about positive impacts on clinical outcomes, but in paediatric practice, where the patient population is smaller and clinical outcomes event rates are low, alternative outcome measures are required to support research and quality improvement beyond large specialist centres, and methodological work on rare events is indicated. With investment in the development of alternative outcome measures and methodologies, programmes like PUMA could improve mortality and morbidity in paediatrics and other patient populations. [ABSTRACT FROM AUTHOR]

Background/aims: The value of using qualitative methods within clinical trials is widely recognised. How qualitative research is integrated within trials units to achieve this is less clear. This paper describes the process through which qualitative research has been integrated within Cardiff University's Centre for Trials Research (CTR) in Wales, UK. We highlight facilitators of, and challenges to, integration. Methods: We held group discussions on the work of the Qualitative Research Group (QRG) within CTR. The content of these discussions, materials for a presentation in CTR, and documents relating to the development of the QRG were interpreted at a workshop attended by group members. Normalisation Process Theory (NPT) was used to structure analysis. A writing group prepared a document for input from members of CTR, forming the basis of this paper. Results: Actions to integrate qualitative research comprised: its inclusion in Centre strategies; formation of a QRG with dedicated funding/roles; embedding of qualitative research within operating systems; capacity building/training; monitoring opportunities to include qualitative methods in studies; maximising the quality of qualitative research and developing methodological innovation. Facilitators of these actions included: the influence of the broader methodological landscape within trial/study design and its promotion of the value of qualitative research; and close physical proximity of CTR qualitative staff/students allowing sharing of methodological approaches. Introduction of innovative qualitative methods generated interest among other staff groups. Challenges included: pressure to under-resource qualitative components of research, preference for a statistical stance historically in some research areas and funding structures, and difficulties faced by qualitative researchers carving out individual academic profiles when working across trials/studies. Conclusions: Given that CTUs are pivotal to the design and conduct of RCTs and related study types across multiple disciplines, integrating qualitative research into trials units is crucial if its contribution is to be fully realised. We have made explicit one trials unit's experience of embedding qualitative research and present this to open dialogue on ways to operationalise and optimise qualitative research in trials. NPT provides a valuable framework with which to theorise these processes, including the importance of sense-making and legitimisation when introducing new practices within organisations. [ABSTRACT FROM AUTHOR]

This action research study considered the role of professional development school (PDS) building liaison as a pivotal gear within the complex learning system of a PDS network. It is based on a series of discussions among a sample of veteran building liaisons as they reflect on the ways in which they have helped shape the learning of the pre-service teachers (PST) in their buildings and the ways in which this learning has been demonstrated in their K-5 students. The study helps to confirm the need for being memorable to students through building relationships and active role modeling. It also reinforces the benefits of sharing with other teachers in order to extend professional learning within a safe and trusting environment. [ABSTRACT FROM AUTHOR]

Microglia are resident macrophages of the CNS that are involved in its development, homeostasis and response to infection and damage. Microglial activation is a common feature of neurological disorders, and although in some instances this activation can be damaging, protective and regenerative functions of microglia have been revealed. The most prominent example of the regenerative functions is a role for microglia in supporting regeneration of myelin after injury, a process that is critical for axonal health and relevant to numerous disorders in which loss of myelin integrity is a prevalent feature, such as multiple sclerosis, Alzheimer disease and motor neuron disease. Although drugs that are intended to promote remyelination are entering clinical trials, the mechanisms by which remyelination is controlled and how microglia are involved are not completely understood. In this Review, we discuss work that has identified novel regulators of microglial activation - including molecular drivers, population heterogeneity and turnover - that might influence their pro-remyelination capacity. We also discuss therapeutic targeting of microglia as a potential approach to promoting remyelination. [ABSTRACT FROM AUTHOR]

Microglia are the resident macrophages of the central nervous system (CNS), implicated in developmental processes, homeostasis, and responses to injury. Derived from the yolk sac during development, microglia self-renew, self-regulate their numbers during homeostatic conditions, and show a robust proliferative capacity even in adulthood. Together with monocyte-derived macrophages (MDM), microglia coordinate the regeneration of CNS myelin around axons, termed remyelination. Gene expression analyses and experimental modelling have identified pro-remyelination roles for microglia/MDM in clearance of myelin debris, secretion of growth factors, and remodelling of the extracellular matrix. Further investigations into the molecular mechanisms controlling these regenerative functions will reveal novel therapeutic strategies to enhance remyelination, by harnessing the beneficial effects of the innate immune response to injury. [ABSTRACT FROM AUTHOR]

Objective Existing theoretical work in decision making and behavior change has focused on how individuals arrive at decisions or form intentions. Less attention has been given to theorizing the requirements that might be necessary for individuals to work collaboratively to address difficult decisions, consider new alternatives, or change behaviors. The goal of this work was to develop, as a forerunner to a middle range theory, a conceptual model that considers the process of supporting patients to consider alternative health care options, in collaboration with clinicians, and others. Methods Theory building among researchers with experience and expertise in clinician–patient communication, using an iterative cycle of discussions. Results We developed a model composed of five inter-related propositions that serve as a foundation for clinical communication processes that honor the ethical principles of respecting individual agency, autonomy, and an empathic approach to practice. We named the model ‘collaborative deliberation.’ The propositions describe: (1) constructive interpersonal engagement, (2) recognition of alternative actions, (3) comparative learning, (4) preference construction and elicitation, and (5) preference integration. Conclusions We believe the model underpins multiple suggested approaches to clinical practice that take the form of patient centered care, motivational interviewing, goal setting, action planning, and shared decision making. [ABSTRACT FROM AUTHOR]

Background: Implementing shared decision making into routine practice is proving difficult, despite considerable interest from policy-makers, and is far more complex than merely making decision support interventions available to patients. Few have reported successful implementation beyond research studies. MAking Good Decisions In Collaboration (MAGIC) is a multi-faceted implementation program, commissioned by The Health Foundation (UK), to examine how best to put shared decision making into routine practice. In this paper, we investigate healthcare professionals' perspectives on implementing shared decision making during the MAGIC program, to examine the work required to implement shared decision making and to inform future efforts. Methods: The MAGIC program approached implementation of shared decision making by initiating a range of interventions including: providing workshops; facilitating development of brief decision support tools (Option Grids); initiating a patient activation campaign ('Ask 3 Questions'); gathering feedback using Decision Quality Measures; providing clinical leads meetings, learning events, and feedback sessions; and obtaining executive board level support. At 9 and 15 months (May and November 2011), two rounds of semi-structured interviews were conducted with healthcare professionals in three secondary care teams to explore views on the impact of these interventions. Interview data were coded by two reviewers using a framework derived from the Normalization Process Theory. Results: A total of 54 interviews were completed with 31 healthcare professionals. Partial implementation of shared decision making could be explained using the four components of the Normalization Process Theory: 'coherence,' 'cognitive participation,' 'collective action,' and 'reflexive monitoring.' Shared decision making was integrated into routine practice when clinical teams shared coherent views of role and purpose ('coherence'). Shared decision making was facilitated when teams engaged in developing and delivering interventions ('cognitive participation'), and when those interventions fit with existing skill sets and organizational priorities ('collective action') resulting in demonstrable improvements to practice ('reflexive monitoring'). The implementation process uncovered diverse and conflicting attitudes toward shared decision making; 'coherence' was often missing. Conclusions: The study showed that implementation of shared decision making is more complex than the delivery of patient decision support interventions to patients, a portrayal that often goes unquestioned. Normalizing shared decision making requires intensive work to ensure teams have a shared understanding of the purpose of involving patients in decisions, and undergo the attitudinal shifts that many health professionals feel are required when comprehension goes beyond initial interpretations. Divergent views on the value of engaging patients in decisions remain a significant barrier to implementation. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To describe the exploratory use of short decision support tools for patients, called Option Grids. Option Grids are summary tables, using one side of paper to enable rapid comparisons of options, using questions that patients frequently ask (FAQs) and designed for face-to-face clinical encounters. To date, most evidence about ‘patient decision aids’ has been based on tools with high content levels, designed for patients to use independently, either before or after visits. Methods: We studied the use of Option Grids in a quality improvement project, collecting field notes and conducting interviews with clinical teams. Results: In the ‘Making Good Decisions in Collaboration’ (MAGIC) program, clinicians found that using Option Grids made it easier to explain the existence of options and reported a ‘handover’ effect, where patient involvement in decision making was enhanced. Conclusion: Option Grids made options more visible and clinicians found it easier to undertake shared decision making when these tools were available. Used in a collaborative way, they enhance patients’ confidence and voice, increasing their involvement in collaborative dialogs. Practice implications: Further work to confirm these preliminary findings is required, to measure processes and to assess whether these tools have similar impact in other clinical settings. [Copyright &y& Elsevier]

The passive corrosion properties of a series of Ni–Cr–Mo alloys were investigated. The alloys studied were C22, C2000, C276, C4 and 625. Potentiostatic experiments at potentials within the passive range were obtained as a function of temperature (25–85 °C) for each alloy. Each specimen was subsequently analyzed by time-of-flight secondary ion mass spectrometry (TOF SIMS) and X-ray photoelectron spectroscopy (XPS). Results indicated that much lower passive dissolution currents, and a much slower attainment of steady-state conditions, were observed on those alloys with >20 wt.% Cr content. These alloys also consistently showed only a minor temperature dependence of the passive current. The surface analyses showed that the high-Cr alloys were able to build thicker oxides with a layered structure consisting of an inner Cr–Ni oxide layer and an outer Mo/Cr oxide. By contrast, such a high-Cr content inner layer and structured elemental distribution were not achieved with alloys having a lower bulk Cr content.For low potentials (200 mV), when Cr dissolution can only occur as Cr(III), additional alloying elements, specifically Mo and W, exert little influence on passive current densities. At 500 mV, a potential at which Cr(VI) release appears to start, the presence of Mo, and especially W, in the outer regions of the oxide suppresses passive dissolution. This may be due to the low dissolution rate of the W-containing surface oxide layer, but some influence of W on the defect density within the oxide cannot be ruled out. The observed temperature dependence for high-Cr alloys (C22, C2000) reflects the lack of steady state and cannot be interpreted as an accurate activation energy. [Copyright &y& Elsevier]

Introduction This study sought to examine the efficacy of integrating medical device alarms into the intercommunication set of a simulated HH-60, allowing medics to hear the alarms over the ambient noise of the aeromedical environment. Materials and Methods U.S. Army critical care flight paramedics were recruited as subjects for this study. Subjects participated in two testing scenarios: One with patient monitor alarms integrated into their communication lines and one without integrated alarms (the control condition). Testing took place in a simulated HH-60 interior with two priority-level patients per testing scenario, one on either side of the interior. Subjects provided care to these two patients for 30 minutes per scenario. After both scenarios were complete, the subjects were given a questionnaire to obtain their feedback on alarm integration. Results Six subjects took part in this study, so the results do not have sufficient power to represent the population. No statistically significant results were found. Looking at the trends in the data, implementing alarm integration showed the indications of reducing reaction time to alarms, decreasing or matching the amount of time spent with the patient monitor, and equivalent amounts of time dedicated to patient treatment when compared to the nonintegrated scenario. The feedback obtained from the subjects provided a list of perceived benefits, drawbacks, and improvements related to the integration of medical device alarms into the intercommunication set. Conclusions Although the study was underpowered, the trends in the data indicate a benefit to the medics when integrating medical device alarms. When coupled with strongly favorable end-user feedback, the results provide justification for pursuing the effort of integrating alarms and performing future studies with improved integration systems to optimize the potential of the system. [ABSTRACT FROM AUTHOR]

Background: Implementing shared decision making into routine practice is proving difficult, despite considerable interest from policy-makers, and is far more complex than merely making decision support interventions available to patients. Few have reported successful implementation beyond research studies. MAking Good Decisions In Collaboration (MAGIC) is a multi-faceted implementation program, commissioned by The Health Foundation (UK), to examine how best to put shared decision making into routine practice. In this paper, we investigate healthcare professionals' perspectives on implementing shared decision making during the MAGIC program, to examine the work required to implement shared decision making and to inform future efforts.Methods: The MAGIC program approached implementation of shared decision making by initiating a range of interventions including: providing workshops; facilitating development of brief decision support tools (Option Grids); initiating a patient activation campaign ('Ask 3 Questions'); gathering feedback using Decision Quality Measures; providing clinical leads meetings, learning events, and feedback sessions; and obtaining executive board level support. At 9 and 15 months (May and November 2011), two rounds of semi-structured interviews were conducted with healthcare professionals in three secondary care teams to explore views on the impact of these interventions. Interview data were coded by two reviewers using a framework derived from the Normalization Process Theory.Results: A total of 54 interviews were completed with 31 healthcare professionals. Partial implementation of shared decision making could be explained using the four components of the Normalization Process Theory: 'coherence,' 'cognitive participation,' 'collective action,' and 'reflexive monitoring.' Shared decision making was integrated into routine practice when clinical teams shared coherent views of role and purpose ('coherence'). Shared decision making was facilitated when teams engaged in developing and delivering interventions ('cognitive participation'), and when those interventions fit with existing skill sets and organizational priorities ('collective action') resulting in demonstrable improvements to practice ('reflexive monitoring'). The implementation process uncovered diverse and conflicting attitudes toward shared decision making; 'coherence' was often missing.Conclusions: The study showed that implementation of shared decision making is more complex than the delivery of patient decision support interventions to patients, a portrayal that often goes unquestioned. Normalizing shared decision making requires intensive work to ensure teams have a shared understanding of the purpose of involving patients in decisions, and undergo the attitudinal shifts that many health professionals feel are required when comprehension goes beyond initial interpretations. Divergent views on the value of engaging patients in decisions remain a significant barrier to implementation. [ABSTRACT FROM AUTHOR]

Background: Widespread implementation of patient engagement by organisations and clinical teams is not a reality yet. The aim of this study is to develop a measure of organisational readiness for patient engagement designed to monitor and facilitate a healthcare organisation's willingness and ability to effectively implement patient engagement in healthcare. Methods: The development of the MORE (Measuring Organisational Readiness for patient Engagement) scale was guided by Weiner's theory of organisational readiness for change. Weiner postulates that an organisation's readiness is determined by both the willingness and ability to implement the change (i.e. in this context: patient engagement). A first version of the scale was developed based on a literature search and evaluation of pre-existing tools. We invited multi-disciplinary stakeholders to participate in a two-round online Delphi survey. Respondents were asked to rate the importance of each proposed item, and to comment on the proposed domains and items. Second round participants received feedback from the first round and were asked to re-rate the importance of the revised, new and unchanged items, and to provide comments. Results: The first version of the scale contained 51 items divided into three domains: (1) Respondents' characteristics; (2) the organisation's willingness to implement patient engagement; and (3) the organisation's ability to implement patient engagement. 131 respondents from 16 countries (health care managers, policy makers, clinicians, patients and patient representatives, researchers, and other stakeholders) completed the first survey, and 72 of them also completed the second survey. During the Delphi process, 34 items were reworded, 8 new items were added, 5 items were removed, and 18 were combined. The scale's instructions were revised. The final version of MORE totalled 38 items; 5 on stakeholders, 13 on an organisation's willingness to implement, and 20 on an organisation's ability to implement patient engagement in healthcare. Conclusions: The Delphi technique was successfully used to refine the scale's instructions, domains and items, using input from a broad range of international stakeholders, hoping that MORE can be applied in a variety of healthcare contexts worldwide. Further assessment is needed to determine the psychometric properties of the scale. [ABSTRACT FROM AUTHOR]

Aims: Aim of this study is to better understand the role of nurses' professional judgment in nurse staffing systems. Design: Qualitative comparative case study design of nurse staffing systems in England and Wales. Methods: Data will be collected through a variety of sources: individual interviews, observations of relevant meetings and analysis of key documents. Ethical approval for the study was granted in August 2020 from The Healthcare Research Ethics Committee (SREC reference: REC741). Data generation will be informed by science and technology studies and practice theories. Discussion: Ensuring adequate numbers of nurses are available to care for patients in response to shifting demand is an international policy priority. Emerging evidence on the use of formal workforce planning methodologies across the developed world highlights both the centrality of nurses' professional judgement in nurse staffing methodologies and the urgent need for theoretically informed research to better understand and conceptualise its contribution to decision‐making. This study is designed to address this gap in understanding. It takes advantage of nurses' experiences of managing the service and staffing impacts of the Covid‐19 pandemic and differences in strategic approaches to nurse staffing systems between England and Wales. Impact: The research will: make visible the knowledge and skills that underpin professional judgement in nurse staffing decisions and provide a conceptual language with which to articulate this;lay the foundations for evidence‐based programmes of nurse education and continuing professional development;furnish the evidence to inform the development of nurse‐led decision support tools to augment professional judgement; andgenerate wider insights into the effectiveness of nurse staffing systems in practice. [ABSTRACT FROM AUTHOR]

Objective: Research is needed to understand how Shared Decision-Making (SDM) is enacted in routine clinical settings. We aimed to 1) describe the process of SDM between clinicians and patients; 2) examine how well the SDM process compares to a prescriptive model of SDM, and 3) propose a descriptive model based on observed SDM in routine practice.Methods: Patients with chronic kidney disease and early stage breast cancer were recruited consecutively via Cardiff and Vale University Health Board (UK) teams. Consultations were audio-recorded, transcribed and thematically analysed.Results: Seventy-six consultations were observed: 26 pre-dialysis consultations and two consultations each for 25 breast cancer patients. Key stages of the 'Three Talk Model' were observed. However, we also observed more elements and greater complexity: a distinct preparation phase; tailored and evolving integrative option conversation; patients and clinicians developing 'informed preferences'; distributed and multi-stage decisions; and a more open-ended planning discussion. Use of decision aids was limited.Conclusion: A more complex picture was observed compared with previous portrayals in current theoretical models.Practice Iimplications: The model can provide a basis for future training and initiatives to promote SDM, and tackle the gap between what is advocated in policy, but rarely achieved in practice. [ABSTRACT FROM AUTHOR]

Background: Shared decision making is considered an important aspect of chronic disease management. We explored the feasibility of routinely measuring kidney patients' involvement in making decisions about renal replacement therapy (RRT) in National Health Service settings. Methods: We disseminated a 17-item paper questionnaire on involvement in decision-making among adult patients with established kidney failurewho made a decision about RRT in the previous 90 days (Phase 1) and patients who had been receiving RRT for 90-180 days (Phase 2). Recruitment rates were calculated as the ratio between the number of included and expected eligible patients (I : E ratio). We assessed our sample's representativeness by comparing demographics between participants and incident patients in the UK Renal Registry. Results: Three hundred and five (Phase 1) and 187 (Phase 2) patients were included. For Phase 1, the I : E ratio was 0.44 (range, 0.08-2.80) compared with 0.27 (range, 0.04-1.05) in Phase 2. Study participants were more likely to be white compared with incident RRT patients (88 versus 77%; P < 0.0001).We found no difference in age, gender or social deprivation. In Phases 1 and 2, the majority reported a collaborative decision-making style (73 and 69%), and had no decisional conflict (85 and 76%); the median score for shared decision-making experience was 12.5 (Phase 1) and 10 (Phase 2) out of 20. Conclusion: Our study shows the importance of assessing the feasibility of data collection in a chronic disease context prior to implementation in routine practice. Routine measurement of patient involvement in established kidney disease treatment decisions is feasible, but there are challenges in selecting the measure needed to capture experience of involvement, reducing variation in response rate by service and identifying when to capture experience in a service managing people's chronic disease over time. [ABSTRACT FROM AUTHOR]

We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10−20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10−13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10−10) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is the major pediatric cancer. At diagnosis, the developmental timing of mutations contributing critically to clonal diversification and selection can be buried in the leukemia's covert natural history. Concordance of ALL in monozygotic, monochorionic twins is a consequence of intraplacental spread of an initiated preleukemic clone. Studying monozygotic twins with ALL provides a unique means of uncovering the timeline of mutations contributing to clonal evolution, pre- and postnatally. We sequenced the whole genomes of leukemic cells from two twin pairs with ALL to comprehensively characterize acquired somatic mutations in ALL, elucidating the developmental timing of all genetic lesions. Shared, prenatal, coding-region single-nucleotide variants were limited to the putative initiating lesions. All other nonsynonymous single-nucleotide variants were distinct between tumors and, therefore, secondary and postnatal. These changes occurred in a background of noncoding mutational changes that were almost entirely discordant in twin pairs and likely passenger mutations acquired during leukemic cell proliferation. [ABSTRACT FROM AUTHOR]

The principles of shared decision making are well documented but there is a lack of guidance about how to accomplish the approach in routine clinical practice. Our aim here is to translate existing conceptual descriptions into a three-step model that is practical, easy to remember, and can act as a guide to skill development. Achieving shared decision making depends on building a good relationship in the clinical encounter so that information is shared and patients are supported to deliberate and express their preferences and views during the decision making process. To accomplish these tasks, we propose a model of how to do shared decision making that is based on choice, option and decision talk. The model has three steps: a) introducing choice, b) describing options, often by integrating the use of patient decision support, and c) helping patients explore preferences and make decisions. This model rests on supporting a process of deliberation, and on understanding that decisions should be influenced by exploring and respecting "what matters most" to patients as individuals, and that this exploration in turn depends on them developing informed preferences. [ABSTRACT FROM AUTHOR]

The principles of shared decision making are well documented but there is a lack of guidance about how to accomplish the approach in routine clinical practice. Our aim here is to translate existing conceptual descriptions into a three-step model that is practical, easy to remember, and can act as a guide to skill development. Achieving shared decision making depends on building a good relationship in the clinical encounter so that information is shared and patients are supported to deliberate and express their preferences and views during the decision making process. To accomplish these tasks, we propose a model of how to do shared decision making that is based on choice, option and decision talk. The model has three steps: a) introducing choice, b) describing options, often by integrating the use of patient decision support, and c) helping patients explore preferences and make decisions. This model rests on supporting a process of deliberation, and on understanding that decisions should be influenced by exploring and respecting 'what matters most' to patients as individuals, and that this exploration in turn depends on them developing informed preferences. [ABSTRACT FROM AUTHOR]

To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 × 10?9) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 × 10?15). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 × 10?7). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights. [ABSTRACT FROM AUTHOR]

A genome-wide association study of chronic lymphocytic leukaemia (CLL) suggested that common variants at 15q25.2 (rs783540) and 18q21.1 (rs1036935) influence CLL. To validate these associations and explore their relationship with CLL risk we genotyped case-control datasets from Poland, UK and Italy totalling 1428 cases and 1920 controls. Combined data from these and previously genotyped series (2503 cases and 5789 controls) provided evidence for an association between 15q25.2 and 18q21.1 loci and CLL risk ( P = 1·10 × 10 and 1·30 × 10 respectively). These data provide further evidence for the involvement of common genetic variants in CLL risk and insight into the biological basis of disease development. [ABSTRACT FROM AUTHOR]

To identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10−8), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10−13) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10−8). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10−50). These data provide new insight into the pathogenesis of cHL. [ABSTRACT FROM AUTHOR]

Women treated at young ages with supra-diaphragmatic radiotherapy for Hodgkin lymphoma (HL) have a highly increased risk of breast cancer. For personalized advice and follow-up regimens for patients, information is needed on how the radiotherapy-related risk is affected by other breast cancer risk factors. Genome-wide association studies have identified 14 independently replicated common single nucleotide polymorphisms that influence breast cancer risk. To examine whether these variants contribute to risk of radiation-associated breast cancer in HL, we analyzed 2 independent case-control series, from the United Kingdom and The Netherlands, totaling 693 HL patients, 232 with breast cancer and 461 without. rsl 21 9648, which annotates the FGFR2 gene, was associated with risk in both series (combined per-allele odds ratio = 1.59, 95% confidence interval: 1.26-2.02; P= .000111). These data provide evidence that genetic variation in FGFR2 influences radiation-induced breast cancer risk. (Blood. 2012;119(4): 1029-1031) [ABSTRACT FROM AUTHOR]

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, Pcombined = 1.88 × 10?14). This finding advances our understanding of the genetic basis of meningioma development. [ABSTRACT FROM AUTHOR]

In the original publication, sixth author’s surname was incorrectly published as “Llyod” instead of “Lloyd”. The correct name should read as “Amy Lloyd”. [ABSTRACT FROM AUTHOR]

Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10−7), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10−7); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10−7 and OR = 1.09, P = 7.4 × 10−8); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 × 10−9), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P < 2.90 × 10−6). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10−4) and DNA mismatch repair genes (P = 6.1 × 10−4) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC. [ABSTRACT FROM AUTHOR]