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Biomedical subjects

P A O'Neill

Publications and source records attributed to P A O'Neill.

At least 19 recordsLinked to original sources
PubMed2006

Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patients.

The anterior gradient protein-2 (AGR2) is inducible by oestrogen and itself can induce metastasis in a rat model for breast cancer. Here, a rabbit antibody to recombinant human AGR2 was used to assess its prognostic significance in a retrospective cohort of 351 breast cancer patients treated by adjuvant hormonal therapy. The antibody stains 66% of breast carcinomas to varying degrees. The percentage of positive carcinoma cells in tumours directly correlates with the level of AGR2 mRNA (Spearman's rank correlation, P = 0.0007) and protein (linear regression analysis r2 = 0.95, P = 0.0002). There is a significant association of staining of carcinomas for AGR2 with oestrogen receptor alpha (ERalpha) staining and with low histological grade (both Fisher's Exact test P<0.0001). In the ERalpha-positive cases, but not the ERalpha-negative cases, when subdivided into the separate staining classes for AGR2, there is a significantly progressive decrease in patient survival with increased staining (log rank test, P = 0.006). The significant association of staining for AGR2 with patient death over a 10-year period (log rank test P = 0.007, hazard ratio = 3) only becomes significant at 6 years of follow-up. This may be due to the cessation of adjuvant hormonal therapy at an earlier time, resulting in adverse re-expression of the metastasis-inducing protein AGR2.

Adult↗
PubMed2005

The ABC's of disaster response.

The readiness of our healthcare facilities to respond to terrorist acts or naturally occurring epidemics and disasters has been at the center of public attention since September 11, 2001. The many other tragic events that have occurred throughout the world since then further reinforce the need for all healthcare facilities and medical personnel to increase their level of preparedness if they wish to optimize outcomes. Maximizing survival rates and minimizing disability during any MCI hinges on rapid, seamless, and coordinated response between first responders and first receivers. The Incident Command System and the HEICS are organizational tools that form the foundation for such a rapid and coordinated response. The ICS provides a simple and adaptable management structure that is capable of being expanded or contracted to meet the needs of a specific situation. The HEICS adapts the ICS into the hospital setting and, in addition to the benefits stated above; its use of the ICS nomenclature and terminology facilitates the communication and the sharing of resources between all agencies and health care institutions involved. A basic knowledge and understanding of the ICS principles and structure is essential for all individuals participating in a disaster response. Previous efforts at disaster preparedness have focused predominantly on the pre-hospital and rescue phase of the disaster response, but a complete and coordinated community response requires creation of integrated disaster plans. True readiness can only be achieved by testing and modifying these plans through integrated simulation drills and table top exercises. Hospital-wide drills are essential to educate all staff members as to their institutional plan and serve as the only substitute at present to first hand experience. At present, there is no evidence-based literature to define what constitutes the best medical response by medical personnel within a disaster setting. This information will likely evolve over the next several decades as we now recognize Disaster Medicine as a separate scientific and medical entity. In the interim, we can develop and modify our response plans based on the "lessons learned" from past experience. Prior events have demonstrated that general surgeons and surgical subspecialists are critical components to a successful hospital response for the vast majority of all mass casualty incidents. Thus, surgeons must take responsibility for increasing their knowledge and understanding of basic disaster management principles and must play an active role in developing their institutional disaster plans.

Disaster Planning↗
PubMed2004

Wild-type oestrogen receptor beta (ERbeta1) mRNA and protein expression in Tamoxifen-treated post-menopausal breast cancers.

This study has tested the hypothesis that comparison of protein and mRNA expression for ERalpha and ERbeta1 by human breast cancers provides novel information relating to the clinical and pathological characteristics of human breast cancers. Expression of ERalpha and ERbeta1 was identified in 167 invasive cancers from postmenopausal women treated only with endocrine therapy. The cohort included 143 cases receiving only adjuvant Tamoxifen following surgery. ERalpha and ERbeta1 expression was analysed by immunohistochemistry and reverse transcription RT-PCR and compared with clinical progression of individual cancers. ERalpha protein was closely associated with the corresponding RNA detected by RT-PCR (Chi-square, P<0.001). In contrast, ERbeta1 protein and mRNA were inconsistent. Although an association was identified between ERalpha and ERbeta mRNAs (Chi-square, P<0.001) and between ERalpha protein and ERbeta1 mRNA (Chi-square, P<0.027), no association was identified for the ERalpha and ERbeta1 proteins detected by immunohistochemistry. ERbeta1 was not associated with outcome. However, in the absence of ERalpha, ERbeta1 protein expression was associated with elevated cell proliferation. There was a trend for the ERbeta1 protein-positive cases to have a worse outcome, both within the group as a whole as well as within the ERalpha-positive Tamoxifen-treated cases. This study has confirmed the hypothesis that expression of ERalpha is an important determinant of breast cancer progression, and has further demonstrated that ERbeta1 may play a role in the response of breast cancers to endocrine therapy.

Antineoplastic Agents, Hormonal↗
PubMed2004

Early carotid surgery in acute stroke: a multicentre randomised pilot study.

BACKGROUND: Standard practice has been to delay carotid endarterectomy (CEA) for 2 months following acute stroke to avoid a perceived risk of cerebral haemorrhage. We investigated whether early CEA reduces early recurrent stroke and improves outcome in partial anterior circulation infarction (PACI). METHODS: Patients with PACI and a Barthel score of >18 before stroke underwent carotid duplex and CT imaging within 7 days of stroke. Forty consenting patients fit for surgery with greater than 70% ipsilateral carotid stenosis were randomised, 19 to 'early' (within 24 h) and 21 to 'delayed' surgery (at 8 weeks). Modified Rankin and Barthel scores were recorded at 1 week, 2 months, 6 and 12 months. RESULTS: Rankin scores improved more rapidly following 'early' surgery to a score of 1 (0-4) at 2 and 6 months compared with 2.5 and 2 (1-4), respectively, for delayed surgery (p < 0.05). Barthel scores were also significantly improved following 'early' CEA at 7 days but both groups reached a median score of 20 by 2 months. Four 'delayed' and 3 'early' patients suffered extension or recurrence of neurological deficits with 1 death in each group. CONCLUSIONS: Early CEA within 7 days of ischaemic stroke improved functional outcome with earlier hospital discharge. A large multicentre study is needed to exclude the possibility that 'early' CEA increases the risk of cerebral haemorrhage or death.

Activities of Daily Living↗
PubMed2004

Increased risk of malignant progression in benign proliferating breast lesions defined by expression of heat shock protein 27.

Heat shock protein 27 (hsp-27) is a regulator of oestrogen receptor (ER) expression and a modulator of intracellular homeostasis. In this laboratory, Shaaban et al demonstrated the importance of ER-alpha, together with Ki67, in enhancing the progression of benign breast lesions of defined morphological types. To better understand the mechanisms by which ER-alpha promotes breast neoplasia, this study was performed to test the hypothesis that the roles of ER-alpha and hsp-27 may be defined by their quantitative expression in proliferative breast lesions of varying histological risk. The expression of hsp-27 was identified using a specific monoclonal antibody and analysed to assess the proportion of positive epithelial cells using digitised morphometric image analysis. The expression of ER-alpha was analysed by immunohistochemistry and Western blotting in a variety of benign (HUMA121) and malignant mammary cell lines, including ER-alpha(+) (MCF7, ZR-75, T47D) and ER-alpha(-) (MDA-MB 231) breast cancer cell lines. The data confirm that, during progression from normal through proliferative breast lesions to in situ cancer, there was a significant increase in both the proportion and the optical density of the epithelial cells expressing hsp-27. The mean levels of expression ranged from 7.4% of the total number of epithelial cells in normal lobules to 25.17% of epithelial cells in hyperplasias of usual type (HUT) to 61.1% of epithelial cells in ductal carcinoma in situ (P<0.001). The study has confirmed the expression of hsp-27 to be closely associated with ER-alpha(+) expression, and that its regulated expression occurs early along the mammary oncogenic pathway, supporting the initial hypothesis. It is our proposal that the differential expression of hsp-27 modulates the phenotypic behaviour of morphologically benign epithelial cells and hence may be an important determinant in initiating, or promoting, a population of human mammary cancers.

Biomarkers, Tumor↗
PubMed2004

Correlation of mRNA for oestrogen receptor beta splice variants ERbeta1, ERbeta2/ERbetacx and ERbeta5 with outcome in endocrine-treated breast cancer.

This study has been performed to test the hypothesis that different oestrogen receptor beta (ERbeta) splice variants may be important determinants of clinical parameters, including outcome, in post-menopausal women with breast cancer receiving adjuvant endocrine treatment but no chemotherapy. Splice variants ERbeta1, ERbeta2 and ERbeta5 have been analysed by semi-quantitative RT-PCR in a cohort of 105 patients with primary breast cancer. Clinical correlates included age, grade, size, nodal status, ERalpha, progesterone receptor, Ki67, relapse-free survival (RFS) and overall survival (OS). Seventy per cent of cases were ERbeta1 positive, 69% ERbeta2 positive and 70% ERbeta5 positive. Within the cohort, 47% were positive for all three variants while 10% were negative for all three. ERbeta1 exhibited no discernible relationship with disease outcome. ERbeta2 and ERbeta5 expression was significantly associated with better RFS (P<0.005), and ERbeta2 with better OS (P=0.0002). In multivariate analysis, ERbeta2 (P=0.006), nodal status and the level of Ki67 expression were independent predictors for RFS while ERbeta2 (P=0.0008) and Ki67 status were independent predictors for OS. In the ERalpha-positive cases, or in the subset of those receiving adjuvant tamoxifen, ERbeta2 was significantly associated with good RFS (P<0.0005) and was the only independent marker of OS. We conclude that precise identification of splice variants of ERbeta are more important assessors than is ERbeta1 alone of the biological status of individual breast cancers, and hence in predicting their response to endocrine therapy.

Alternative Splicing↗
PubMed2003

Can undergraduate education have an effect on the ways in which pre-registration house officers conceptualise communication?

AIMS: In 1994 Manchester Medical School introduced a learner-centred course using problem-based learning (PBL), which emphasises effective communication skills. This study explored how 2 cohorts of graduates conceptualised communication within their role as pre-registration house officer (PRHOs). METHODS: Graduates from the last year of the traditional and first year of the new course were interviewed 3 months after starting work. They were asked how well their courses had prepared them for working as PRHOs and were given a specific question about communication skills. Interviews were tape-recorded, transcribed, coded and analysed. RESULTS: In all, 24 traditional course graduates (TCGs) and 23 new course graduates (NCGs) were interviewed. Traditional course graduates tended to conceptualise communication as informing people rather than as involving negotiation or having therapeutic effects. Most TCGs considered good communicators 'were born that way' and did not think communication skills could be learned. Many NCGs had a richer concept of communication that recognised communication has therapeutic benefits for patients and involved negotiation. They understood it was possible to teach communication skills. However, a minority of NCGs conceptualised communication in a similar way to TCGs. CONCLUSION: Our study suggests that the new course has helped NCGs acquire a more complex concept of communication in their role as PRHOs.

Cohort Studies↗
PubMed2002

The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists.

Genetic variants are risk factors for coronary disease, but their role in recurrent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIbalpha; platelet ligands beta-fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and P-selectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P = 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone (chi(2) = 20.4, 10 df, P = 0.04). There was a significant interaction of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P = 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treatment-associated bleeding among coronary patients.

Alanine↗
PubMed2002

Small-group work and assessment in a PBL curriculum: a qualitative and quantitative evaluation of student perceptions of the process of working in small groups and its assessment.

The problem based learning (PBL) curriculum at Manchester emphasizes small-group work. This is supported through group assessment where students assess key aspects of their group's function. In the study described here the authors evaluated students' perceptions of both PBL group work and what a group assessment needs to assess. They aimed to produce a description of the cognitive and motivational influences on group process and unpack the ways they contribute to a successful PBL group so that the kinds of skills an effective assessment should assess could be identified. Focus groups and a questionnaire were used to generate the data. The focus group results indicate that students support PBL group work as a method of learning, and that those groups that work cooperatively are perceived as facilitating the most motivating learning environment. The students supported the assessment being summative and felt that it could be simplified to measure: behavioural skills contributing to maximizing motivation of the group process; and cognitive skills relating to the content of the group discussion. The questionnaire results also supported the use of a summative assessment of small-group work that evaluates the domains of group process and the content of the group discussion.

Adult↗
PubMed2001

How well prepared are graduates for the role of pre-registration house officer? A comparison of the perceptions of new graduates and educational supervisors.

OBJECTIVE: The principal aim of undergraduate medical education is to produce competent pre-registration house officers (PRHOs). We examined and compared the perceptions of graduates and educational supervisors concerning how well prepared graduates were for their first post. METHODS: A postal questionnaire was sent to house officers who had graduated from Manchester 3 months earlier and also to educational supervisors of PRHOs in the North-west Region. The questionnaires were based on the competencies set out by the General Medical Council of the United Kingdom. RESULTS: The response rates were 66% from the graduates and 76% from the supervisors. Of the 18 broad areas of competence listed, only four were rated more than 'quite well prepared' by at least 50% of the graduates ('understanding disease processes', 'communicating effectively', 'awareness of limitations' and 'working in a team'). Similarly, more than half of educational supervisors rated graduates as more than quite competent in only three areas ('awareness of limitations', 'keeping accurate records' and 'working in a team'). Within the competencies surveyed, there were differences between the perceptions of graduates and educational supervisors on the preparedness of graduates for the skills they may require as a pre-registration house officer. CONCLUSION: Overall, given that most graduates and supervisors perceived the preparedness as 'quite well' or less, the undergraduate course had only partially met its objectives. A mismatch in ratings could be attributed to either inappropriate expectations on the part of the educational supervisors or the graduates or an inaccurate assessment by either group of respondents.

Attitude of Health Personnel↗
PubMed2001

Students' conceptual model of a good community attachment.

BACKGROUND: In 1994, Manchester University Medical School introduced a new integrated curriculum using problem-based learning and which places an increased emphasis on community-based education. AIMS: Students commonly use a particular label ("a good GP" (general practitioner)) to describe a positive experience in the community. The purpose of the study was to explore what students mean by "a good GP" and how this relates to their perceptions of the value of the community aspect of the course. METHOD: Three single-year focus groups were run with year 3, 4 and 5 students. A model was then derived which was explored and checked against the views of a cross-year focus group. RESULTS: A theoretical model based on student conceptualization of "a good GP" was developed. "A good GP" was found to consist of the GP as a teacher, as a role model and as an indicator of a positive learning environment. With regard to "good teacher", students felt that the GP's enthusiasm about teaching and involving the student in an active learning process was important. For "good role model", students emphasized communication skills and non-judgmental attitudes. With regard to "good learning environment", a friendly atmosphere, variety of activities, and flexibility shown by the staff of the health centre were important. CONCLUSIONS: Students hold a complex conceptual model of "a good GP" which the label does not convey. We suggest that for evaluations of student experiences it is important to explore in depth what students mean by particular terms or labels.

Attitude of Health Personnel↗
PubMed2000

Evaluation of an integrated curriculum using problem-based learning in a clinical environment: the Manchester experience.

DESCRIPTION OF COURSE: In 1994, a new problem-based leaning (PBL) curriculum for year 1 medical students was introduced at the University of Manchester. The use of PBL has continued into the clinical clerkships. Year 3 of the curriculum is based entirely in a clinical environment with PBL groups meeting in three teaching hospitals. During this year, all students undertake two integrated 14-week modules with overarching themes. Each week, groups of eight students discuss a trigger problem connected to the relevant theme. The steps the groups use in the PBL process have been amended to encourage students to link their discussion with clinical experience. EVALUATION: At the end of each module, all 309 students were requested to complete an evaluation questionnaire. The response rates were 80% (n=247) and 89% (n=275) for the two core modules. RESULTS: The students have remained 'happy with the way the course is going' (83% at the end of module 2). They were also asked to rate a number of statements on a 5-point Likert scale (5=strongly agree). Concerning PBL, the students remained confident about working in a group (median 4), producing a set of learning objectives (median 4) and linking clinical experience with other knowledge (median 4). However, there were changes over the year. Fewer students agreed at the end of module 2 that 'the working problems were stimulating' (P=0.002) or 'motivated them to learn' (P < 0.001), but the clinical firms were seen as providing more appropriate experience (P=0.01) and being aware of the new curriculum and responding to it (P=0.018). We also surveyed the PBL tutors and had 65 returns from 78 people involved in the 38 PBL groups in year 3. The great majority of these are doctors employed by the National Health service. Virtually all the responders were happy to continue being a tutor (97%) and would recommend it to a colleague (93%). CONCLUSIONS: The evaluation has been positive with PBL having been successfully implemented in a clinical environment. We have identified significant changes over the year, which we need to address as we consolidate the curriculum.

Clinical Clerkship↗
PubMed2000

The role of basic sciences in a problem-based learning clinical curriculum.

BACKGROUND: Very little is known about the use of problem-based learning (PBL) during the later years of the undergraduate medical course and how it influences further acquisition of basic science knowledge. Similarly to many other Faculties, the PBL approach is used at Manchester in years 1 and 2, but more unusually, the curriculum continues to be centred on PBL in the clinical modules. OBJECTIVES: To explore whether and how basic science learning was continued in year 3 of the PBL clinical curriculum. METHODS: 10 of the weekly problems from the two core modules in year 3 were analysed to determine: (a) whether the design teams were using basic science objectives in devising the problems, and (b) whether PBL student groups were setting basic science learning objectives. The basic science knowledge of year 3 and 4 students was also measured. RESULTS: Similar numbers of objectives were being set by the management groups for each weekly problem (Heart, lung and blood (HLB) module, median 15, range 11-20; Nutrition, metabolism and excretion (NME) module, median 13, range 9-21). In the basic sciences, there was a median of 3 objectives per problem (range 0-6) in the NME module, but only 1 objective (0-2) per problem in the HLB module. The objectives set by six PBL groups in each module were analysed. Overall, agreement was reached on 130 occasions (62%) between the design team basic science objectives and those set for themselves by the student groups. In addition, there was a median of 2 (range 1-8) new basic science objectives brought out by the PBL groups that were not listed by the HLB module design team. In the NME module, there was again a median of 2 new objectives (range 0-6). The performance of year 3 and year 4 students in the multiple-choice questions progress test was analysed. For the 65 basic science questions, the year 3 mark was 40.8 +/- 12.3% compared with 57.1 +/- 12.3% for year 4 (P < 0.0001). CONCLUSIONS: (a) The design teams are setting basic science objectives; (b) the working problems are triggering students to set learning objectives in the basic sciences; (c) most of the objectives being set by the design teams are being triggered in the majority of group sessions; (d) the students knowledge of basic sciences increases in years 3-4.

Curriculum↗
PubMed2000

The combination of bedside swallowing assessment and oxygen saturation monitoring of swallowing in acute stroke: a safe and humane screening tool.

BACKGROUND: dysphagia is common in acute stroke. Accurate detection of the presence or absence of aspiration by bedside swallowing assessment is difficult without objective methods, tending to over-diagnose aspiration. As a result, some patients suffer restricted oral intake unnecessarily. OBJECTIVE: we examined the predictive values of pulse oximetry and speech and language therapy bedside swallowing assessment in the detection of aspiration compared with videofluoroscopy. DESIGN: a double-blind observational study. SETTING: two university teaching hospitals. SUBJECTS: we studied 53 patients whose acute strokes were confirmed by computed tomography scan. METHODS: Each subject had initial standard bedside swallowing assessment, closely followed by simultaneous and mutually blinded pulse oximetry, swallowing assessment and videofluoroscopy. RESULTS: 15 of 53 subjects aspirated. Bedside swallowing assessment and saturation assessment at > or = 2% desaturation gave good sensitivity (80% and 87% respectively), but low positive predictive values (50% and 36% respectively). Both assessments mistook laryngeal penetration for aspiration. Re-analysis with aspiration +/- penetration as a new endpoint improved bedside swallowing assessment positive predictive values to 83% (chi2 =3.59, P=0.032). Sensitivity of saturation assessment was maintained at 86%, positive predictive values of saturation assessment improved to 69% (chi2=6.74, P=0.009). The combination of bedside swallowing assessment and saturation assessment versus aspiration + penetration gave a positive predictive value of 95%. CONCLUSIONS: screening by saturation assessments detects 86% of aspirators/penetrators and should be followed immediately by bedside swallowing assessment, as the combination of the two assessments gives the best positive predictive value. For patients with acute stroke, we advocate a 10 ml water-swallow screening test with simultaneous pulse oximetry by suitably trained medical and nursing staff. Use of this screening test would improve dysphagia detection whilst minimizing unnecessary restriction of oral intake in stroke patients.

Acute Disease↗