Search

Contains fulltext : 292919.pdf (Publisher’s version ) (Open Access) BACKGROUND: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. METHODS: The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. FINDINGS: In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24). INTERPRETATION: Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for. FUNDING: Supported by the Welsh Government and Fight for Sight (24WG201).

This article critically explores the Foucauldian concept of “counter-conduct”, which has recently been applied to the study of resistance in international relations (IR). Whilst a counter-c...

Increasingly, health professional training involves the use of educational technologies through what is broadly termed "Technology-Enhanced Learning" (TEL). TEL includes hardware, such as computers and mobile devices, and software, such as software applications (apps), learning management systems, and discussion boards. For many years, TEL has formed an integral part of health professional programs and is growing in acceptance, if not expectation, in postgraduate training and continuing education. TEL generally aims to be flexible, engaging, learner focused and interactive, and may involve collaboration and communication. It offers many benefits for learning and teaching, whether used on its own or in conjunction with face-to-face teaching through blended learning. The ubiquity of mobile devices in clinical settings means TEL is ideal for busy clinicians, both as learners and teachers. TEL enables participants to learn at a time and place that is convenient to them, so learners living in geographically dispersed locations can access standardized courses. To realize these potential benefits, we recommend that those developing TEL programs for health professionals take a systematic approach to planning, development, implementation, and evaluation. To that end, we propose 10 principles: clarify purpose and conduct a needs assessment; allocate adequate time and technology; incorporate proven approaches to improve learning; consider the need for a skills component; enable interaction between learners and with others; create different resources for different groups; pilot before implementing; incorporate measures to retain learners; provide opportunities for revision to aid retention; and evaluate learning outcomes, not just satisfaction.

Aim The continuing existence of ‘teaching by humiliation’ of medical students and junior doctors in Australia has recently been highlighted in a number of research publications and media reports. This study investigates medical students’ experiences of being intimidated or humiliated during their clinical rotations in Australian hospitals in paediatrics and adult medicine. Methods From factors identified in earlier research, a two-page survey was developed for administration at two Australian medical schools. Administered in Semester 2 of 2014, students were invited to add their own free-text comments at the conclusion of 17 closed questions. Using thematic analysis of the qualitative data, the researchers identified the common themes in the students’ free-text comments, which are reported in this paper. Results We found five main themes in the qualitative data: a spectrum of interpretations of and responses to ‘teaching by humiliation’, an accepted means of enculturating the young, teachers’ techniques for asking questions, the victims and perpetrators of mistreatment and the variance of prevalence in different contexts. Conclusion Research shows the persistence of ‘teaching by humiliation’, even in paediatrics, particularly when doctors are questioning students in ways that shame them for their lack of knowledge. Given the many personal and professional costs of these practices, this cycle of mistreatment needs to be brought to an end. There is a need for students’ reports of intimidation and humiliation to be acknowledged; the offending practices need to be interrupted, and more effective and respectful approaches to teaching need to be adopted.

111 Background: High tumor mRNA levels of the EGFR ligands, AREG and EREG are associated with anti-EGFR agent response in patients (pts) with RAS-wt mCRC, regardless of tumor location. However, ligand RNA assays have not been adopted into routine clinical practice due to issues with analytical precision and practicality. Here we test whether AREG and EREG expression assessed by IHC can predict benefit from Pan. Methods: A retrospective biomarker study within the PICCOLO trial (NCT00389870; irinotecan [Ir] ± Pan in fluoropyrimidine-resistant RAS-wt mCRC). AREG and EREG positive tumor cells were assessed by IHC in all RAS-wt patients with available tumor tissue. Pathologists annotated tumor areas on digital images of glass slides. Artificial intelligence (AI) algorithms calculated the percentage of tumor cells staining positive for AREG and EREG within the tumor areas. More than 50% AREG and/or EREG tumor cell positivity was regarded as high ligand expression. The primary endpoint was progression-free survival (PFS) and secondary endpoints were RECIST response rate (RR) and overall survival (OS). Results: 274 RAS-wt pts had available tumor tissue. High ligand expression (n = 132) was associated with significant PFS benefit from IrPan compared with Ir (8.0 vs 3.2 months; HR 0.54 [0.37-0.79]; p = 0.001); whereas low ligand expression (n = 142) was not (3.4 vs 4.4 months; HR 1.05 [95% CI, 0.74-1.49]; p = 0.78). The ligand-treatment interaction was significant (p = 0.02) and independent of BRAF-mutation status and primary tumor location. Likewise RR was significantly improved in pts with high ligand expression (IrPan vs Ir: 48% vs 6%; risk ratio, 7.8 [2.90-20.69]; p < 0.0001) but not those with low ligand expression (IrPan vs Ir: 25% vs 14%; risk ratio, 1.8 [95% CI, 0.89-3.65]; p = 0.10) (interaction p = 0.01). Lesser effect was seen on OS. Conclusions: IHC assessment of AREG and EREG identified pts who did or did not benefit from Pan, as has been previously demonstrated through mRNA quantification. IHC represents a more practicable technique as it can be provided at the point of care and is associated with shorter turn-around times. AREG and EREG IHC may be of use in routine practice to identify patients who would benefit from anti-EGFR therapy and those for whom alternative treatment strategies should be explored.

INTRODUCTION: This study investigated the perspectives on pedagogy held by medical teachers in hospitals. METHODS: The teachers were interviewed after they had been observed in both clinical and classroom settings. RESULTS: The study showed the teachers' reliance on the relational aspects of pedagogy more than on technical pedagogical knowledge. Teachers referred to their aims and approaches as "interactive," but this does not refer to any deliberate pedagogical design or acts. Asking questions was the technique used most commonly but not always skillfully, and they cited influences from the past rather than the present or the future. DISCUSSION: This research suggests the pedagogic approach of these medical teachers is "humanistic." It emphasizes personal and interpersonal factors, meaningful learning, and the affective, as well as cognitive aspects of clinical knowledge. It also captures a commitment to nonthreatening, nonhumiliating environments. Acknowledgment of this particular pedagogical perspective, it is argued, could better connect the health professional teachers with the education and development missions of universities, professional bodies, and governments. The teachers' expressed values and goals offer a new starting point for faculty development. Their reliance on the relational over the technical and on their own biographical experience, could be more respectfully valued and addressed to advance a more productive balance with the technical pedagogical elements that often concern educationalists, researchers, and administrators.

In this paper, a new theoretical framework for curricula is proposed as a means of advancing the potential for health professional graduates to contribute optimally in the contemporary world of complex health care. A new theoretical approach to curriculum is needed to provide for a comprehensive and integrated view of the diversity in people and populations. These subject areas require rigor and strength equivalent to the strong and well-established foundations of the biosciences and clinical practice. A rigorous and coherent approach would replace what is often an ad hoc response to diverse and marginalized people and populations in existing curricula. The current approach has not had sufficient impact on health disparities. This paper presents the case for adopting an ‘intersectional’ framework for health professional curricula to move the voices and experiences of marginalized groups from the periphery to the center of the curriculum conversations. The pillars of that framework are described and illustrated with examples, and the implications and expected benefits of adopting such a framework are discussed. To illustrate the limitations of the current approach to curriculum development and the need for and likely benefits of the proposed framework, the paper draws on the situation of Australian Indigenous peoples. Refereed/Peer-reviewed

Barrett and McColl raise the question posed in the title of their commentary to highlight the value of attending to interactions between students and their learning environment.

Background: Disparity in health status and healthcare outcomes is widespread and well known. This holds true for Indigenous peoples in many settings including Australia and Hawaii. While multi-factorial, there is increasing evidence of health practitioner contribution to this disparity. This research explored senior medical students' clinical decision-making processes. Methods: A qualitative study was conducted in 2014 with 30 final year medical students from The University of Melbourne, Australia, and The John Burns Medical School, Hawaii, USA. Each student responded to questions about a paper-based case, first in writing and elaborated further in an interview. Half the students were given a case of a patient whose ethnicity was not declared; the other half considered the patient who was Native Hawaiian or Australian Aboriginal. A systematic thematic analysis of the interview transcripts was conducted. Results: The study detected subtle biases in students' ways of talking about the Indigenous person and their anticipation of interacting with her as a patient. Four main themes emerged from the interview transcripts: the patient as a person; constructions of the person as patient; patient-student/doctor interactions; and the value of various education settings. There was a strong commitment to the patient's agenda and to the element of trust in the doctor-patient interaction. Conclusion: These findings will help to advance medical curricula so that institutions graduate physicians who are increasingly able to contribute to equitable outcomes for all patients in their care. The study also draws attention to subtle biases based on ethnicity that may be currently at play in physicians' practices.

For over four decades, there have been efforts to specify the types of knowledge that medical students need, how that knowledge is acquired and how its constituent parts are related. It is one of the areas of continuing concern underlying medical education reform. Despite their importance to medical students' learning and development, the perspectives of medical teachers in hospitals are not always considered in such discourse. This study sought to generate an understanding of these teachers' values, perspectives and approaches by listening to them and seeing them in their everyday teaching work, finding and understanding the meanings they bring to the work of medical teaching in hospitals. In interviews, all of the teachers talked more about the optimal forms of knowledge that are important for students than they talked about the form of the teaching itself. Many revealed to students what knowledge they do and do not value. They had a particular way of thinking about clinical knowledge as existing in the people and the places in which the teaching and the clinical practice happen, and represented this as 'real' knowledge. By implication, there is other knowledge in medical education or in students' heads that is not real and needs to be transformed. Their values, practices and passions add texture and vitality to existing ways of thinking about the characteristics of clinical knowledge, how it is depicted in the discourse and the curriculum and how it is more dynamically related to other knowledge than is suggested in traditional conceptualizations of knowledge relationships.

SummaryAim Following research about workplace constraints reducing the effectiveness of teaching and the motivation to teach, this study sought to understand how medical teachers in hospitals respond to the institutional context for their teaching of medical students. Methods Through purposive sampling, younger and older male and female teachers in a range of medical and surgical paediatrics subspecialties participated in this qualitative study. We drew on ethnographic methods in interviews so that answers to the questions came from the teachers’ own emphases. The systematic coding and categorising procedures used in the inductive analysis of the interview transcripts reflect the constant comparison approach of grounded theory, locating features, patterns and conceptual categories. Results We identified four main concepts: teachers’ goals and motivations; their approaches to teaching; teachers’ preferences; and, finally, as discussed in this article, the teachers’ perceptions of contextual and institutional pressures in hospital-based medical teaching and related compromises. The teachers perceive constraints resulting from the various mismatches that they experience, a loss of autonomy, and the paucity of acknowledgement and resources. They suggest that the compromises they make in response are both pedagogical and institutional. Conclusion We conclude that professional development is not enough to address these issues: the conditions for medical teaching and teachers in hospitals require workplace responses to enable a more productive connection between the students, curriculum and pedagogy. In particular, teachers’ responsibilities in teaching and curriculum development need to be acknowledged, and practising teachers need to be supported and included in the education mission.

Context The black box that is student learning in clinical environments is an ongoing research project. Our previous research showed that despite the time that students are given to learn with, about and from patients, some lack confidence for those encounters and see few patients. The study reported here investigated individual and environmental factors affecting medical students' self-directed learning time in hospital. Methods We studied second year students in the four-year postgraduate Melbourne Medical School programme as they undertook the first of their four 9-week hospital placements in medical wards. Each week approximately 10 hours of structured teaching is offered; the remaining time is spent in self-directed learning. Over six weeks, we observed 31 medical students and interviewed 17 of them. The interviews were subjected to content analysis procedures and the observation notes added contextual information to what was said in interviews. We considered the findings through the Experience-based Learning framework. Results We found four main themes in the data: finding and contacting patients challenges all students and overwhelms some; the educational design of the placement is a flawed navigational device providing inadequate clarity and security; the physical and social terrain of a large tertiary hospital is replete with obstacles making it easy for some students to stumble and retreat; finally, any positive connection with peers, staff and patients is empowering. Conclusions This study throws light on to the uncertain path of the novice clinical learner illuminating both the intractable aspects of hospital environments and opportunities for pedagogical and affective supports that can compensate. The processes and conditions for self-directed learning time need attention in order to provide for a safe, efficient or successful clerkship experience for all students. Particular effort is needed to sensitively identify those individuals who struggle and suffer on the journey, and provide appropriate support.

Bibl iography: Barrett, Jenny: Queer Cinema: Schoolgirls, Vampires and Gay Cowboys, INSEP, Vol. 2, Issue 1/2014, pp. 115-117. https://doi.org/10.3224/insep.v2i1.17068

This article was migrated. The article was marked as recommended. AimThe accreditation of medical schools is a key leadership role for the Australian Medical Council (AMC) and its counterparts in other jurisdictions. The aim of our research was to identify how the inclusion of Indigenous health in the accreditation standards has influenced the reporting of activity related to Indigenous health in medical schools.MethodA bi-national review was conducted of the AMC reporting of Indigenous health education initiatives against the accreditation standards from January 2007 to December 2014. Also reviewed was the AMC monitoring of medical schools that occurs via schools' Comprehensive Reports and Progress Reports.ResultsThe study showed that the inclusion of Indigenous-specific standards leads to specific reporting on aspects related to Indigenous peoples in accreditation assessments and monitoring of medical school programs. Where areas in the accreditation standards did not include Indigenous-specific requirements, AMC reporting was unlikely to mention Indigenous matters. ConclusionsThe continuing commitment by the AMC - and comparable bodies in other jurisdictions - to assessing medical education programs against specific Indigenous health standards, represents significant leadership in educating a medical workforce committed to ongoing improvement of Indigenous peoples' health.

OBJECTIVE: To generate a contemporary understanding of "teaching by humiliation" as experienced by medical students in Australia. DESIGN, SETTING AND PARTICIPANTS: In this pilot study, we surveyed final-stage medical students from two Australian medical schools about their experiences of teaching by humiliation during their adult and paediatric clinical rotations. The students were invited to complete the anonymous survey at the end of their paediatric rotation in Semester 2 of 2013. We used descriptive statistics to analyse quantitative data, and a grounded theory approach to analyse qualitative data. MAIN OUTCOME MEASURES: Student reports of experiencing or witnessing teaching by humiliation during their adult and paediatric clinical rotations. RESULTS: Of 151 students invited to participate, 146 (96.7%) completed the survey. Most students reported experiencing (108; 74.0%) or witnessing (118; 83.1%) teaching by humiliation during adult clinical rotations. Smaller but still sizeable proportions had experienced (42; 28.8%) or witnessed (64; 45.1%) it during their paediatric clinical rotation. The humiliating and intimidating behaviours students experienced were mostly more subtle than overt and included aggressive and abusive questioning techniques. The students' responses to these practices ranged from disgust and regret about entering the medical profession to endorsement of teachers' public exposure of a student's poor knowledge. CONCLUSIONS: Practices associated with humiliating medical students persist in contemporary medical education. These practices need to be eradicated, given the evidence that they affect students' learning and mental health and are dissonant with formal professionalism curricula. Interventions are needed to interrupt the transgenerational legacy and culture in which teaching by humiliation is perpetuated. Language: en

The present study addresses graduate satisfaction with the university, perceptions of employment preparation at the local level (and beyond), and the relationship between the two. Results suggest that there exist divergent levels of satisfaction with various aspects of the university and that perceptions of employment preparation differ on the basis of whether employment is at the local, national, or international level. Importantly, graduates' satisfaction with academic resources, student support services, and the institution's development of competencies significantly predicted perceived employment preparation. Females and graduates of vocationally oriented (rather than generalist) faculties also reported greater employment preparation. Discussion focuses on aspects of the university that are influential in assisting graduates' transition from the university to the workplace.

In literal terms, no one alive in the twenty-first century remembers the American Civil War. William Marvel’s 1991 article in Blue and Gray dated the death of the last Civil War veteran, a Union man, at 1956. 1 A child born on the day of the Confederate surrender would have had to have lived to just shy of 135 years to have seen in the present century. This war has, however, remained part of a national and international memory despite there being no living person today able to say “I was there.” What we “remember,” then, is perhaps more accurately described as what we perceive or believe about the Civil War, principally composed of a plethora of stories, images, and icons, factual and fictional, from a relatively finite range of public and pub­lished forms, among these being school textbooks, memorial and heritage sites, memoirs, academic publishing, television documentaries, and narrative cinema. 2

Introduction: The aim of this narrative review of the literature was to use systematic search and review procedures to describe a contemporary understanding of the expression “teaching by humiliation.” Method: A search was conducted of MEDLINE, 1990‒2013, using search terms humiliat*, intimidat*, harass* and abus*. Three hundred and forty-one papers were located; however, only papers related to medical students and medical trainees were considered. Papers dealing with substance abuse, patient abuse and sexual harassment were excluded. Of the 341 papers located, only 30 met the criteria for inclusion. One reviewer/author read all 30 papers; both reviewers/authors annotated 15 papers each, and subsequently agreed on the following categories for the systematic review: clarifying terminology, identifying specific behaviours, the extent of the problem, explanations posited, and finally, the effects of humiliation and abuse. Results: The review confirmed that the expression “teaching by humiliation” appears in the literature but that “abuse” and “mistreatment” are more common terms for medical teachers’ behaviours towards students. These behaviours range from yelling, shouting and physical abuse to subtle undermining and demeaning language and practices. The behaviours are widespread and persistent across many countries, and victims suffer personal and professional effects. Conclusion: There is ongoing concern in the literature about the culture of medical education that perpetuates these practices and the failure to interrupt that culture despite decades of research and commentary.

Summary Context: Many university courses employ simulated patients to work with students in the development of communication skills. Our challenge was to build a sustainable programme that could be adapted for medical, nursing and allied health staff, and groups of students, on our hospital campus. Innovation: In recognition of the need to provide practice opportunities for junior medical staff to hone their capacity to communicate effectively with parents, we employed professional actors who are also qualified teachers. Junior doctors have multiple opportunities over their training time to work one-to-one with an actor-tutor in the role of simulated parent. The simulated parents are skilled in helping the trainees reflect on the conversation, and the trainees are given a recording of their sessions for further reflection and feedback from a colleague. This model has been adapted to meet the ‘topic’ needs and scheduling requirements of other staff and hospital-based student groups. Discussion: In adapting the original medical staff programme, we came to appreciate not only the logistical but also the ethical considerations inherent in a simulated parent/patient programme. Our guide highlights the importance of safeguarding the educational integrity of the design, maintaining the fidelity of the simulations and ensuring the safety of all involved.

Background CDKN2A mutations confer a substantial risk of cutaneous melanoma; however, the magnitude of risk is uncertain. Methods The study estimated the hazard ratio (HR) and the average age specific cumulative risk (ie, penetrance) of reported melanoma for CDKN2A mutation carriers in case families using a modified segregation analysis of the first and higher degree relatives of 35 population-based cases. The study sample included 223 relatives of 13 melanoma cases diagnosed when aged 18–39 years from Melbourne, Sydney and Brisbane, Australia, and 322 relatives of 22 melanoma cases diagnosed at any age from Yorkshire, UK. Results The estimated HR for melanoma for mutation carriers relative to the general population decreased with regions of increasing ambient ultraviolet (UV) irradiance, being higher for the UK than Australia (87, 95% CI 50 to 153 vs 31, 95% CI 20 to 50, p=0.008), and across Australia, 49 (95% CI 24 to 98) for Melbourne, 44 (95% CI 22 to 88) for Sydney, and 9 (95% CI 2 to 33) for Brisbane (p=0.02). Penetrance did not differ by geographic region. It is estimated that 16% (95% CI 10% to 27%) of UK and 20% (95% CI 13% to 30%) of Australian CDKN2A mutation carriers would be diagnosed with melanoma by age 50 years, and 45% (95% CI 29% to 65%) and 52% (95% CI 37% to 69%), respectively, by age 80 years. Conclusions Contrary to the strong association between UV radiation exposure and melanoma risk for the general population, CDKN2A mutation carriers appear to have the same cumulative risk of melanoma irrespective of the ambient UV irradiance of the region in which they live.

Considering the privileged space that the western enjoyed in the twentieth century in the forging and endorsing of a certain kind of American national identity, this article argues that Poitier's presence as a frontier hero in some of the most overlooked and underestimated films of the man's career is of remarkable significance. Despite the exasperation of some critics at the formulaic nature of his three westerns, I will argue that the casting of Poitier as the westerner creates a disturbance in the construction of the on-screen American ancestor, raising vital issues concerning American masculinity, racism, miscegenation and freedom.

3583 Background: EGFR pathway activation is important in aCRC, but EGFR expression is not predictive for anti-EGFR drug efficacy. Signalling occurs across ErbB receptors and EGFR may mediate oncoge...

Tissue inhibitors of metalloproteinases (TIMP1, TIMP2, TIMP3) are naturally occurring inhibitors of matrix metalloproteinases (MMPs). It has been proposed that MMPs have a role in weakening the fibrous cap and subsequent plaque rupture. We hypothesized that TIMP polymorphisms could predispose to premature coronary artery disease. As a first step, we examined the relevant loci using a linkage approach. Sibling pairs recruited for the British Heart Foundation (BHF) Family Heart Study with premature coronary artery disease were examined. Two to three microsatellite markers were examined per TIMP gene. These markers were either intragenic or very close to the locus encoding for the gene. Products were analyzed by capillary gel electrophoresis. Single and multipoint linkage analysis based on the likelihood ratio test was performed using SPLINK and Mapmaker/Sibs software; 417 families were genotyped consisting of 385 sibling pairs, 27 trios, and five sets of four siblings. We were unable to detect linkage of premature coronary artery disease to loci encoding for TIMP1-3. Polymorphisms of the tissue inhibitors of MMP genes do not predispose to premature coronary artery disease in an epidemiologically significant way.

Objective To undertake a systematic whole-genome screen to identify regions exhibiting genetic linkage to rheumatoid arthritis (RA). Methods Two hundred fifty-two RA-affected sibling pairs from 182 UK families were genotyped using 365 highly informative microsatellite markers. Microsatellite genotyping was performed using fluorescent polymerase chain reaction primers and semiautomated DNA sequencing technology. Linkage analysis was undertaken using MAPMAKER/SIBS for single-point and multipoint analysis. Results Significant linkage (maximum logarithm of odds score 4.7 [P = 0.000003] at marker D6S276, 1 cM from HLA–DRB1) was identified around the major histocompatibility complex (MHC) region on chromosome 6. Suggestive linkage (P < 7.4 × 10−4) was identified on chromosome 6q by single- and multipoint analysis. Ten other sites of nominal linkage (P < 0.05) were identified on chromosomes 3p, 4q, 7p, 2 regions of 10q, 2 regions of 14q, 16p, 21q, and Xq by single-point analysis and on 3 sites (1q, 14q, and 14q) by multipoint analysis. Conclusion Linkage to the MHC region was confirmed. Eleven non-HLA regions demonstrated evidence of suggestive or nominal linkage, but none reached the genome-wide threshold for significant linkage (P = 2.2 × 10−5). Results of previous genome screens have suggested that 6 of these regions may be involved in RA susceptibility.

3520 Background: RNA expression of epiregulin (EREG) ligands EREG and/or amphiregulin (AREG) has shown correlation with the efficacy of EGFR-targeted therapy in advanced colorectal cancer (aCRC). T...

Background The discovery and validation of prognostic and predictive biomarkers in advanced colorectal cancer is crucial for the personalisation of therapy. Inflammation-based prognostic scores have been developed, including the neutrophil lymphocyte ratio (NLR), and the derived NLR (dNLR) calculated using a differential white cell count. The NLR has been assessed in several cancers; in a retrospective series of advanced colorectal cancer, higher NLR was associated with reduced survival and poorer outcomes with chemotherapy. We aimed to validate the usefulness of the dNLR as a prognostic and a predictive biomarker to anti-epidermal growth factor receptor (EGFR) agents in advanced colorectal cancer. Methods We studied patients from a phase 3, open-label, randomised controlled trial that assessed the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer (PICCOLO trial). The prognostic analysis included all patients for whom dNLR data were available; a subset with KRAS wild-type tumours randomised to standard irinotecan with or without panitumumab was also analysed for predictive value. The dNLR was calculated from the prerandomisation blood count and categorised as high (≥2) or low ( Findings 1159 patients were included in the prognostic analysis, and 444 in the predictive analysis. In multivariate analysis, high dNLR was independently associated with reduced overall survival compared with low dNLR (hazard ratio 1·59, 95% CI 1·32–1·78; p KRAS, BRAF, NRAS , and PIK3CA ), and in the subset of 323 patients in this all-wild-type category panitumumab had a more marked effect on tumour response rate in patients with low dNLR (odds ratio 7·4, p Interpretation The dNLR seems to offer the clinician useful prognostic information. Since this information can easily be calculated from routine clinical data, its integration into routine patient assessment should be considered after further validation. We did not demonstrate significant predictive value for anti-EGFR therapy, but our finding of higher response with panitumumab in patients with a low dNLR is hypothesis generating. Further investigation in datasets from randomised controlled trials and exploratory translational work are warranted. Funding Cancer Research UK, Yorkshire Cancer Research.

Coronary artery disease (CAD) and its most important complication, myocardial infarction (MI), are the leading cause of premature death in the Western world. CAD has a substantial genetic basis, especially when it occurs early. We investigated the genetic determinants of premature CAD by performing a genomewide linkage analysis of 4,175 affected subjects from 1,933 families recruited throughout the United Kingdom. Each family had at least two available siblings with CAD, with validated onset before age 66 years. Linkage analysis was performed using 416 microsatellite markers. We observed suggestive linkage, for both CAD and MI, to a region on chromosome 2. For CAD, a LOD score of 1.86 was observed at marker D2S2271, which, in an ordered subset analysis, increased to 2.70 in families (n=1,698) with a minimum age at diagnosis of 56 years or younger. For MI, an overlapping peak with a LOD score of 1.15 was observed at marker D2S2216, which increased to 2.1 in families (n=801) with a minimum age at diagnosis of 59 years or younger. Exclusion mapping showed that 100% of the autosomal genome could be excluded for locus-specific sibling relative risks of 1.5 and 1.6 for CAD and MI, respectively. The region identified on chromosome 2 overlaps linked regions observed in two other smaller genome scans for CAD. Together, these findings strongly suggest that there is a locus on chromosome 2 that influences coronary atherosclerosis risk. The exclusion of a common locus that increases risk of CAD to siblings by >50% has important implications for strategies for further defining the genetic basis of CAD.