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SUMMARY Many cases of giardiasis in the UK are undiagnosed and among other things, diagnosis is dependent upon the readiness of GPs to request a specimen. The aim of this study is to assess the rate of specimens requested per GP practice in Central Lancashire, to examine the differences between GP practices and to estimate the pattern of unexplained spatial variation in the practice rate of specimens after adjustment for deprivation. To achieve this, we fitted a set of binomial and Poisson regression models, with random effects for GP practice. Our analysis suggests that there were differences in the rate of specimens by GP practices (P < 0·001) for a single year, but no difference in the proportion of positive tests per specimen submitted or in the rate of positive specimens per practice population. There was a difference in the cumulative rate of positive specimens per practice population over a 9-year period (P < 0·001). Neither the specimen rate per practice for a single year nor the cumulative rate of positive specimens over multiple years demonstrated significant spatial correlation. Hence, spatial variation in the incidence of giardiasis is unlikely to be confounded by variation in GP rate of specimens.

To assess whether residential proximity to industrial incinerators in England is associated with increased risk of cancer incidence and mortality.

To assess whether residential proximity to industrial incinerators in England is associated with increased risk of cancer incidence and mortality.

We present a comprehensive review of multivariate geostatistical models, focusing on the bivariate case. We compare in detail three approaches, the linear model of coregionalisation, the common component model and the kernel convolution approach, and discuss similarities between them. We demonstrate the merits of the common component class of models as a flexible means for modelling bivariate geostatistical data of the type that frequently arises in environmental applications. In particular, we show how kernel convolution can be used to approximate the common component model, and demonstrate the method using a data-set of calcium and magnesium concentrations in soil samples. We then apply the model to a study of domestic radon concentrations in the city of Winnipeg, Canada, in which exposure was measured at two sites (bedroom and basement) in each residential location. Our analysis demonstrates that in this study the correlation between the two sites within each house dominates the short-range spatial correlation typical of the distribution of radon.

Standard analyses of spatial data assume that measurement and prediction locations are measured precisely. In this paper we consider how appropriate methods of estimation and prediction change when this assumption is relaxed and the locations are subject to positional error. We describe basic models for positional error and assess their impact on spatial prediction. Using both simulated data and lead concentration pollution data from Galicia, Spain, we show how the predictive distributions of quantities of interest change after allowing for the positional error, and describe scenarios in which positional errors may affect the qualitative conclusions of an analysis. The subject of positional error is of particular relevance in assessing the exposure of an individual to an environmental pollutant when the position of the individual is tracked using imperfect measurement technology.

The aim of this study was to evaluate survival and success rates following autotransplantation of permanent maxillary canine teeth. Sixty-three cases of maxillary canine autotransplantation from 49 subjects (mean age at transplantation 21.8 years, range 13–42.1 years) undertaken between 1977 and 2003 were collected as part of an audit project of transplantation success. All maxillary canines had complete root development at the time of transplantation. The sample was divided into two groups, a matched case–control study to compare 27 unilateral transplanted canines with the non-transplanted canine on the contralateral side, and all 63 transplanted canines with no controls. Teeth were assessed clinically using established criteria for success: tooth presence for survival and resorption, mobility, probing pocket depth (PPD), gingival bleeding, vitality, and colour. Radiographic investigation for success assessed internal and external inflammatory resorption (including the amount) bone levels and any signs of pathology. Data were described with descriptive statistics and analytical tests were used to assess frequencies of occurrence. The survival rate was 83 per cent with an average duration of 14.5 years in situ. Thirty-eight per cent of the transplants were deemed successful. There were statistically significant associations between the transplanted and non-transplanted teeth in PPD (P = 0.006), gingival bleeding (P = 0.006), vitality (P = 0.004), and colour (P = 0.002). Autotransplantation of impacted maxillary canines can be successful in the long term and may be indicated in selected cases. Although the rate for complete success in this study was low (no signs of resorption, mobility, and sound periodontal tissues), the survival rate can be considered favourable when evaluating autotransplantation as a treatment option for grossly malpositioned canines with little scope for orthodontic alignment.

The aim of this study was to determine the incidence of facial clefting in Cambridge, UK, using multiple resources of ascertainment and to relate the findings to antenatal ultrasound screening (AUS) detection rates. AUS records from an obstetric ultrasound department, post-natal records from the regional craniofacial unit, and autopsy reports of foetuses over 16 weeks’ gestational age from a regional pathology department from 1993 to 1997 were retrospectively reviewed. Cross-referencing between the three data sets identified all cases of facial clefts. Of 23 577 live and stillbirths, 30 had facial clefts. AUS detected 17 of these. Sixteen of the 30 had isolated facial clefts. Others had associated anomalies, chromosomal defects, or syndromes. Percentages and confidence intervals were calculated from the above data. Twenty-one resulted in live births, seven terminations, and two foetal deaths. Overall, detection rate by AUS was 65 per cent [67 per cent isolated cleft lip, 93 per cent cleft lip and palate (CLP), and 22 per cent isolated cleft palate], with no false positives. The incidence of facial clefts was 0.127 per cent (95 per cent confidence interval 0.089–0.182 per cent); the incidence for isolated CLP was lower than previously reported: 0.067 per cent (0.042–0.110 per cent). With one exception, all terminations were in foetuses with multiple anomalies. The figures presented will enable joint CLP clinics to give parents information of termination rates. The study allows pre-pregnancy counselling of families previously affected by clefting about the reliability of AUS detection rates.

Aims and method To systematically review the published literature with respect to formulating a dose-response curve for flupentixol decanoate. A systematic literature search using the Cochrane Database was performed for studies that published both dosage information and data on relapse rates. Results The data showed modest effects of dose on survival rates. Increasing dose may be associated with increased survival rates up to around 50-60 mg of flupentixol decanoate every 4 weeks. There was no evidence of increased survival rates at higher doses and higher doses may be associated with lower rates of survival. There is considerable uncertainty as to the true effects of dose of flupentixol decanoate on relapse rates. Clinical implications There is no evidence that survival rates improve for doses above 50-60 mg every 4 weeks. These doses are much lower than doses commonly prescribed. Clinicians may wish to consider these data when prescribing flupentixol decanoate.

Developing more effective behavioural interventions requires an understanding of the mechanisms of behaviour change, and methods to rigorously test their theoretical basis. The delivery and theoretical basis of an intervention protocol were assessed in ProActive, a UK trial of an intervention to increase the physical activity of those at risk of Type 2 diabetes (N = 365). In 108 intervention sessions, behaviours of facilitators were mapped to four theories that informed intervention development and behaviours of participants were mapped to 17 theoretical components of these four theories. The theory base of the intervention specified by the protocol was different than that delivered by facilitators, and that received by participants. Of the intervention techniques delivered, 25% were associated with theory of planned behaviour (TPB), 42% with self-regulation theory (SRT), 24% with operant learning theory (OLT) and 9% with relapse prevention theory (RPT). The theoretical classification of participant talk showed a different pattern, with twice the proportion associated with OLT (48%), 21% associated with TPB, 31% with SRT and no talk associated with RPT. This study demonstrates one approach to assessing the extent to which the theories used to guide intervention development account for any changes observed.

Background Declining physical activity is associated with a rising burden of global disease. Efforts to reverse this trend have not been successful. We aimed to assess the efficacy of a facilitated behavioural intervention to increase the physical activity of sedentary individuals at familial risk of diabetes. Methods We enrolled 365 sedentary adults who had a parental history of type 2 diabetes. They were recruited from either diabetes or family history registers at 20 general practice clinics in the UK. Eligible participants were randomly assigned to one of two intervention groups, or to a comparison group. All participants were posted a brief advice leaflet. One intervention group was offered a 1-year behaviour-change programme, to be delivered by trained facilitators in participants' homes, and the other the same programme by telephone. The programme was designed to alter behavioural determinants, as defined by the theory of planned behaviour, and to teach behaviour-change strategies. The principal outcome at 1 year was daytime physical activity, which was objectively measured as a ratio to resting energy expenditure. Analysis was by intention to treat. This study is registered as ISRCTN61323766. Findings Of 365 patients, we analysed primary endpoints for 321 (88%) for whom we had data after 1 year of follow-up. At 1 year, the physical-activity ratio of participants who received the intervention, by either delivery route, did not differ from the ratio in those who were given a brief advice leaflet. The mean difference in daytime physical-activity ratio, adjusted for baseline, was −0·04 (95% CI −0·16 to 0·08). The physical-activity ratio did not differ between participants who were delivered the intervention face-to-face or by telephone (mean difference −0·05; 95% CI −0·19 to 0·10). Interpretation A facilitated theory-based behavioural intervention was no more effective than an advice leaflet for promotion of physical activity in an at-risk group; therefore healt

Aims To assess the cardiovascular disease (CVD) risk of people with screen-detected Type 2 diabetes and to estimate the risk reduction achievable through early intensive pharmacological intervention. Methods In ADDITION-Cambridge, diabetic patients were identified among people aged 40–69 years through a stepwise screening procedure including a risk score, random and fasting capillary blood glucose, HbA1c and oral glucose tolerance test. In those without prior macrovascular disease, 10-year CVD risk was computed using UK Prospective Diabetes Study (UKPDS) and Framingham engines. The absolute risk reduction achievable and its plausible range were predicted using relative risk reductions for individual therapies from published trials and sensitivity analysis. Results Of the 867 individuals with undiagnosed diabetes, 19% had pre-existing CVD, 97% were overweight or obese, 86% had hypertension, 75% had dyslipidaemia, 20% had microalbuminuria and 18% were smokers. Of those with hypertension, 35% were not prescribed drugs and 42% were suboptimally treated. Of participants with dyslipidaemia, 68% were not prescribed medications and 22% were poorly controlled. Median 10-year CVD risk was 34.0%[interquartile range (IQR) 26.2–44.6] in men and 21.5% (IQR 15.7–28.7) in women using the UKPDS engine; 38.6% (IQR 27.8–53.0) in men and 24.6% (IQR 17.2–32.9) in women using Framingham equations. In the most conservative scenario (no additive effect of therapies), the absolute risk reduction achievable through multifactorial therapy ranged from 4.9 to 9.5% (UKPDS) and from 5.4 to 10.5% (Framingham). The corresponding ranges of numbers needed to treat were 11–20 and 10–19. Conclusions People with screen-detected diabetes have an adverse cardiovascular risk profile, which is potentially modifiable through application of existing treatment recommendations.

Assessing fidelity of behavioural interventions is important, but demanding and rarely done. This study assessed adherence to behaviour change techniques used in an intervention to increase physical activity among sedentary adults ( ProActive ; N = 365). Transcripts of 108 sessions with a sub-sample of 27 participants were assessed. An independent assessor coded adherence of four ‘facilitators’ who delivered the intervention to 208 protocol-specified facilitator behaviours (e.g. ‘elicit perceived advantages of becoming more active’) in four key sessions. Four raters classified the 208 behaviours under 14 techniques (e.g., goal setting, use of rewards) to enable calculation of adherence to techniques. Observed adherence to techniques across participants was modest (median 44%, IQR 35–62%), and lower than that reported by facilitators. Adherence differed between facilitators (range: 26–63%) and decreased across the four sessions (mean drop 9% per session, 95% confidence interval 7–11%). In this small sample facilitator adherence was unrelated to (change in) participants’ physical activity or its cognitive predictors: Attitudes, subjective norm, perceived behavioural control and intention. Future research should investigate causal pathways between fidelity indicators and outcomes in larger samples and develop and test less intensive measures of fidelity.

Studies investigating associations between air pollution exposure and health outcomes benefit from the estimation of exposures at the individual level, but explicit consideration of the spatio-temporal variation in exposure is relatively new in air pollution epidemiology.We address the problem of estimating spatially and temporally varying particulate matter concentrations (black smoke = BS = PM4) using data routinely collected from 20 monitoring stations in Newcastle-upon-Tyne between 1961 and 1992.We propose a two-stage strategy for modelling BS levels. In the first stage, we use a dynamic linear model to describe the long-term trend and seasonal variation in area-wide average BS levels. In the second stage, we account for the spatio-temporal variation between monitors around the area-wide average in a linear model that incorporates a range of spatio-temporal covariates available throughout the study area, and test for evidence of residual spatio-temporal correlation.We then use the model to assign time-aggregated predictions of BS exposure, with associated prediction variances, to each singleton pregnancy that occurred in the study area during this period, guided by dates of conception and birth and mothers’ residential locations. In work to be reported separately, these exposure estimates will be used to investigate relationships between maternal exposure to BS during pregnancy and a range of birth outcomes. Our analysis demonstrates how suitable covariates can be used to explain residual spatio-temporal variation in individual-level exposure, thereby reducing the need to model the residual spatio-temporal correlation explicitly.

Background: Transjugular liver biopsy (TJLB) can be performed to obtain more than two cores safely. This advantage has not been evaluated in terms of diagnostic accuracy or grading/staging evaluation. Aim: To evaluate whether three separate cores of TJLB provide more histological information compared with two or one cores. Methods: Twenty-three patients, who had three separate passes, with each core ≥7mm in length using a 19G Tru-cut needle, were evaluated. Each TJLB was blindly coded; the pathologist randomly assessed: (a) each core separately covering the other two, (b) two cores simultaneously covering the third and (c) the three cores together for diagnostic yield, inflammation and fibrosis. Results: The mean TJLB length was 32±5.5mm. In 12 one-core (52%) and 18 2-core (78%) assessments, diagnosis (mainly cirrhosis) was made correctly in each core. The within-patient standard deviations for one-core vs two-core assessment were similar for grading (0.42 and 0.47, respectively), but higher for staging (0.39 and 0.15, respectively). Staging was underestimated in assessing one-core and less for two cores compared to three cores. Conclusion: Three non-fragmented cores (each core ≥7mm in length) of TJLB can be considered a minimum requirement for histological assessment, giving better reproducibility in diagnosis as well as for inflammation and fibrosis.

Background & Objectives The aim of this study was to apply three simple risk - scoring systems to prospectively collected data on all elective open Abdominal Aortic Aneurysm (AAA) operations in the Cambridge Academic Vascular Unit over a 6 - year period (January 1998 to January 2004), to compare their predictive values and to evaluate their validity with respect to prediction of mortality and post-operative complications. Methods 204 patients underwent elective open infra-renal AAA repair. Data were prospectively collected and risk assessment scores were calculated for mortality and morbidity according to the Glasgow Aneurysm Score (GAS), VBHOM (Vascular Biochemistry and Haematology Outcome Models) and Estimation of Physiologic Ability and Surgical Stress (E-PASS). Results The mortality rate was 6.3% (13/204) and 59% (121/204) experienced a post-operative complication (30-day outcome). For GAS, VBHOM and E-PASS the receiver operating characteristics (ROC) curve analysis for prediction of in-hospital mortality showed area under the curve (AUC) of 0.84 (95% confidence interval [CI], 0.76 to 0.92; p < 0.0001), 0.82 (95% CI, 0.68 to 0.95; p = 0.0001) and 0.92 (95% CI, 0.87 to 0.97; p < 0.0001) respectively. There were also significant correlations between post-operative complications and length of hospital stay and each of the three scores, but the correlation was substantially higher in the case of E-PASS. Conclusions All three scoring systems accurately predicted the risk of mortality and morbidity in patients undergoing elective open AAA repair. Among these, E-PASS seemed to be the most accurate predictor in this patient population.

Background The Estimation of Physiologic Ability and Surgical Stress (E-PASS) score was designed on the premise that the balance between the patient’s physiologic reserve capacity and the surgical stress inflicted at operation was important in the occurrence of postoperative complications. The aim of this study was to assess its value in predicting mortality and morbidity after open elective abdominal aortic aneurysm (AAA) repair. Methods E-PASS data items were collected prospectively in a group of 204 patients undergoing elective open AAA repair over a 6-year period. The operative morbidity and mortality rates were compared with the preoperative risk score (PRS), surgical stress score (SSS) and comprehensive risk score (CRS) of E-PASS. The group comprised 180 (88%) males and the median age was 73 (range 44 to 86) years. Results There were 13 (6%) deaths and 121 (59%) experienced a postoperative complication. As the PRS, SSS and CRS increased, the incidence of postoperative morbidity and mortality significantly increased (P < .0001). Overall mean CRS was .52 (±.27). Mean CRS in the groups of patients who survived and died were .49 (±.24) and .98 (±26), respectively. PRS, SSS, and CRS all had extremely good predictive power for both mortality and morbidity as demonstrated by high areas under the receiver operator curve (range .799 to .953). CRS also showed a strong statistically significant association with the severity of postoperative complication (P < .0001) and length of hospital stay (P < .0001). Conclusions The E-PASS model appears to be a promising method of predicting death and the development of postoperative complications in patients undergoing elective open AAA surgery. It requires further validation in arterial surgery at different geographical locations.

Activation of mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) growth signalling is coupled to increased cell proliferation in prostate cancer (PCa). Dysregulation of the DNA replication licensing pathway, a critical step in growth control downstream of transduction signalling pathways, is associated with development of PCa. In this study we have investigated linkages between the MEK5/ERK5 pathway and DNA replication licensing during prostate carcinogenesis. The effects of increased MEK5/ERK5 signalling on the expression of replication licensing factors Mcm2 and geminin and the proliferation marker Ki67 were studied in an ecdysone-inducible system expressing a constitutively activated mutant of MEK5 in EcR293 cells and in stable ERK5 over-expressing PC3 clones. In parallel, expression of these biomarkers in PCa biopsy specimens (n=58) was studied and compared to clinicopathological parameters. In both in vitro systems induction of MEK5 expression resulted in increased levels of phosphorylated ERK5 and Mcm2, geminin and Ki67 proteins. In PCa specimens average Mcm2 expression was greater than Ki67 and geminin expression (median labelling index (LI) 36.7, 18.1, and 3.4% respectively), consistent with their differential expression according to growth status (P<0.0001). Mcm2, geminin and Ki67 expression were significantly associated with Gleason grade (P=0.0002, P=0.0003, P=0.004); however there was no link with T or M stage. There was a significant relationship between increasing ERK5 expression and increasing Mcm2 (P=0.003) and Ki67 (P=0.009) expression, with non-significant trends seen with increasing MEK5 expression. There were significant associations between Gleason grade and the number of cells traversing G1 phase (Ki67LI-gemininLI; (P=0.001)), with high ERK5 levels associated with both an increase in replication licensed but non-cycling cells (Mcm2LI-Ki67LI; (P=0

Purpose: DNA replication licensing factors and Aurora kinases play critical roles in maintaining genomic integrity. We used multiparameter analyses of these cell cycle regulatory proteins to investigate their role in the progression of epithelial ovarian carcinoma (EOC). Experimental Design: In a cohort of 143 patients, we linked the protein expression profiles of the proliferation marker Ki67, the replication licensing factors Mcm2 and geminin, and the Aurora A and B kinases to tumor DNA ploidy status and clinical outcome. Results: Ki67, Mcm2, geminin, and Aurora A and B are significantly associated with tumor grade and ploidy status (P < 0.0001). Aurora A and its substrate H3S10ph are also significantly associated with Federation of International Obstetricians and Gynecologists tumor stage (P = 0.006 and P = 0.002, respectively). Aurora A and tumor ploidy status are predictive of disease-free survival in this cohort [hazard ratio (HR), 1.29; 95% confidence intervals (95% CI), 1.06-1.58, P = 0.01 and HR, 1.80 (1.05-3.08), P = 0.03, respectively], with Aurora A of particular prognostic importance in early stage disease [HR, 1.72 (1.19-2.48), P = 0.004 for disease-free survival and HR, 1.81 (1.14-2.87), P = 0.01 for overall survival]. Conclusions: Our data show that Ki67, Mcm2, geminin and Aurora A and B can be used as an adjunct to conventional prognostic indicators and as an aid to develop a tumor progression model for EOC. Dysregulation of Aurora A seems to be an early event in EOC with a key role in tumor progression. In view of present drug development programs for specific Aurora kinase inhibitors, our findings have important implications for the use of Aurora A as a biomarker and as a potential therapeutic target.

The objective was to evaluate the effect of an assessment strategy using the computer decision support system (the GRAIDS software), on the management of familial cancer risk in British general practice in comparison with best current practice. The design included cluster randomised controlled trial, and involved forty-five general practice teams in East Anglia, UK. Randomised to GRAIDS (Genetic Risk Assessment on the Internet with Decision Support) support (intervention n=23) or comparison (n=22). Training in the new assessment strategy and access to the GRAIDS software (GRAIDS arm) was conducted, compared with an educational session and guidelines about managing familial breast and colorectal cancer risk (comparison) were mailed. Outcomes were measured at practice, practitioner and patient levels. The primary outcome measure, at practice level, was the proportion of referrals made to the Regional Genetics Clinic for familial breast or colorectal cancer that were consistent with referral guidelines. Other measures included practitioner confidence in managing familial cancer (GRAIDS arm only) and, in patients: cancer worry, risk perception and knowledge about familial cancer. There were more referrals to the Regional Genetics Clinic from GRAIDS than comparison practices (mean 6.2 and 3.2 referrals per 10 000 registered patients per year; mean difference 3.0 referrals; 95% confidence interval (CI) 1.2–4.8; P=0.001); referrals from GRAIDS practices were more likely to be consistent with referral guidelines (odds ratio (OR)=5.2; 95% CI 1.7–15.8, P=0.006). Patients referred from GRAIDS practices had lower cancer worry scores at the point of referral (mean difference -1.44 95% CI -2.64 to -0.23, P=0.02). There were no differences in patient knowledge about familial cancer. The intervention increased GPs' confidence in managing familial cancer. Compared with education and mailed guidelines, assessment including computer decision support increased the number and quality of

Aim To compare the effect of an initial early computed tomography (CT) examination versus standard practice (SP) on the length of hospital stay, diagnostic accuracy, and mortality of adults presenting with acute abdominal pain. Materials and methods Two hundred and five adults presenting with acute abdominal pain were randomized to undergo an early CT examination or current SP, which comprised supine abdominal and erect chest radiography. One hundred and ninety-eight patients (99 in each arm) were included in the analysis. The primary endpoint was the duration of inpatient stay; secondary endpoints were diagnostic certainty and mortality. Results There was no significant difference in the length of hospital stay between the two arms (p = 0.20). At randomization 36% (35 of 96) of CT patients and 49% (48 of 98) of SP patients were correctly diagnosed; 24 h after randomization the correct diagnosis had been established in 84% of CT patients and 73% of SP patients. This refinement in diagnostic certainty was significantly better in the CT group (p < 0.001). There was no difference in mortality between the two trial arms (p = 0.31). Conclusion Early abdominal CT in patients with acute abdominal pain improves diagnostic certainty, but does not reduce the length of hospital stay and 6 month mortality.

Mcm2–7 (MCM) proteins are part of the origin licensing machinery that regulates initiation of DNA replication. Geminin is a licensing repressor and prevents reinitiation of DNA replication during S–G2–M phase by blocking reloading of Mcm2–7 at replication origins. Here, we have analysed these replication licensing factors (RLFs) to determine whether the pathway becomes deregulated during mammary carcinogenesis, and have assessed their potential value as prognostic markers. Protein expression profiles were generated for Ki67, Mcm2, geminin, HER-2, ER and PR in a series of reduction mammoplasty (n=18) and breast cancer specimens (n=120), and compared to clinicopathological parameters. A large proportion of epithelial cells of the terminal duct lobular unit reside in a primed 'replication licensed' but not proliferating state. This state is characterised by Mcm2 expression and absence of Ki67 and the S/G2/M marker geminin. In breast cancers, increasing tumour grade is associated with increased Ki67, Mcm2 and geminin expression. The Mcm2/Ki67 ratio decreases through the grades, indicating a shift from a predominantly licensed state to an actively proliferating state. This shift is associated with an increase in the geminin/Ki67 ratio, signifying a shortening of G1 phase in breast cancer cells. Ki67, Mcm2 and the Mcm2/Ki67 ratio are statistically significantly associated with the Nottingham Prognostic Index (NPI), but geminin and the geminin/Ki67 ratio are not. Ki67, Mcm2 and Mcm2/Ki67 are highly correlated with one another, with Mcm2 being the single most important predictor of NPI score (P<0.001). However, only 12% of variation in NPI is explained by Mcm2, as the labelling index for this marker is approaching 100% for many of the high-grade tumours. The origin licensing phenotypes of normal breast and breast cancers therefore relate to their cellular differentiation status, and high-level MCM expression in more poorly differentiated tumours severely constrains their us

The DNA replication (or origin) licensing machinery ensures precise duplication of the genome and contributes to the regulation of proliferative capacity in metazoa. Using an in vitro fibroblast model system coupled to a cell-free DNA replication assay, we have studied regulation of the origin licensing pathway during exit from and re-entry into the mitotic cell cycle. We show that in the quiescent state (G0) loss of proliferative capacity is achieved in part through down-regulation of the replication licensing factors Cdc6 and Mcm2–7. The origin licensing repressor geminin is absent in quiescent fibroblasts, suggesting that this powerful inhibitor of the licensing machinery is not required to suppress proliferative capacity in G0. Geminin expression is induced at a late stage in the G0–S transition post pre-RC assembly. Ectopic geminin can block re-acquisition of DNA replication competence during re-entry into the cell cycle, indicating that geminin levels must be tightly down-regulated for escape from G0. Analysis of geminin levels in thyroid shows that geminin expression is suppressed in anatomical compartments/tissues harbouring quiescent cells, confirming our in vitro data. Spatio-temporal control of geminin expression may therefore be of particular relevance for multi-potential stem cells which cycle infrequently. In support of this hypothesis, we have identified a unique population of cells in the putative stem cell niche of intestinal epithelium that are unlicensed and lack geminin expression, a prerequisite for successful re-entry into cycle. Our data argue that the prolonged cell cycle times observed for intestinal stem cells could be due to exit of progenitor cells from cycle into an unlicensed “out-of-cycle” state, a powerful mechanism by which rapidly proliferating tissues may resist genotoxic insult.

Objectives To compare patients' enablement and satisfaction after teaching and non-teaching consultations. To explore patients' views about the possible impact that increased community based teaching of student doctors in their practice may have on the delivery of service and their attitudes towards direct involvement with students. Design Observational study using validated survey instruments (patient enablement index—PEI, and consultation satisfaction questionnaire—CSQ) administered after teaching consultations and non-teaching consultations. Ten focus groups (two from each practice), comprising five with patients participating in prearranged teaching sessions and five with patients not participating in these. Setting Five general practices in west Suffolk and southern Norfolk, England, that teach student doctors on the Cambridge graduate medical course. Participants 240 patients attending teaching consultations (response rate 82%, 196 patients) and 409 patients attending non-teaching consultations (response rate 72%, 294 patients) received survey instruments. Ten focus groups with a total of 34 patients participating in prearranged teaching sessions and 20 patients not participating in these. Main outcome measures Scores on the patient enablement index and consultation satisfaction questionnaire, analysed at the level of all patients, allowing for age, sex, general practitioner, and practice, and at the level of the individual general practitioner teacher. Qualitative analysis of focus group data. Results Patients' enablement or satisfaction was not reduced after teaching consultations compared with non-teaching consultations (mean difference in scores on the patient enablement index and consultation satisfaction questionnaire with adjustment for confounders 2.24% and 1.70%, respectively). This held true for analysis by all patients and by general practitioner teacher. Qualitative data showed that patients generally supported the teaching of student doctors in th