Sub-1.4 cm3 capsule for detecting labile inflammatory biomarkers in situ.

Transient molecules in the gastrointestinal tract such as nitric oxide and hydrogen sulfide are key signals and mediators of inflammation. Owing to their highly reactive nature and extremely short lifetime in the body, these molecules are difficult to detect. Here we develop a miniaturized device that integrates genetically engineered probiotic biosensors with a custom-designed photodetector and readout chip to track these molecules in the gastrointestinal tract. Leveraging the molecular specificity of living sensors1, we genetically encoded bacteria to respond to inflammation-associated molecules by producing luminescence. Low-power electronic readout circuits2 integrated into the device convert the light emitted by the encapsulated bacteria to a wireless signal. We demonstrate in vivo biosensor monitoring in the gastrointestinal tract of small and large animal models and the integration of all components into a sub-1.4 cm3 form factor that is compatible with ingestion and capable of supporting wireless communication. With this device, diseases such as inflammatory bowel disease could be diagnosed earlier than is currently possible, and disease progression could be more accurately tracked. The wireless detection of short-lived, disease-associated molecules with our device could also support timely communication between patients and caregivers, as well as remote personalized care.

Solving the Polyploid Mystery in Health and Disease.

Polyploidy (the more than doubling of a cell's genome) frequently arises during organogenesis, tissue repair, and age-associated diseases. Despite its prevalence, major gaps exist in how polyploid cells emerge and affect tissue function. Studies have begun to elucidate the signals required for polyploid cell growth as well as the advantages and disadvantages of polyploidy in health and disease. This review highlights the recent advances on the role and regulation of polyploidy in Drosophila and vertebrate models. The newly discovered versatility of polyploid cells has the potential to provide alternative strategies to promote tissue growth and repair, while limiting disease and dysfunction.

Co-designed weight management intervention for women recovering from oestrogen-receptor positive breast cancer.

BACKGROUND: Weight gain is commonly observed during and after breast cancer treatment and is associated with poorer survival outcomes, particularly in women with oestrogen receptor-positive (ER +) disease. The aim of this study was to co-design (with patients) a programme of tailored, personalised support (intervention), including high-quality support materials, to help female breast cancer patients (BCPs) with ER + disease to develop the skills and confidence needed for sustainable weight loss.  METHODS: ER + BCPs were recruited from two UK National Health Service (NHS) Trusts. The selection criteria included (i) recent experience of breast cancer treatment (within 36 months of completing primary treatment); (ii) participation in a recent focus group study investigating weight management perceptions and experiences; (iii) willingness to share experiences and contribute to discussions on the support structures needed for sustainable dietary and physical activity behaviour change. Co-design workshops included presentations and interactive activities and were facilitated by an experienced co-design researcher (HH), assisted by other members of the research team (KP, SW and JS). RESULTS: Two groups of BCPs from the North of England (N = 4) and South Yorkshire (N = 5) participated in a two-stage co-design process. The stage 1 and stage 2 co-design workshops were held two weeks apart and took place between Jan-March 2019, with each workshop being approximately 2 h in duration. Guided by the Behaviour Change Wheel, a theoretically-informed weight management intervention was developed on the basis of co-designed strategies to overcome physical and emotional barriers to dietary and physical activity behaviour change. BCPs were instrumental in designing all key features of the intervention, in terms of Capability (e.g., evidence-based information, peer-support and shared experiences), Opportunity (e.g., flexible approach to weight management based on core principles) and Motivation (e.g., appropriate use of goal-setting and high-quality resources, including motivational factsheets) for behaviour change. CONCLUSION: This co-design approach enabled the development of a theoretically-informed intervention with a content, structure and delivery model that has the potential to address the weight management challenges faced by BCPs diagnosed with ER + disease. Future research is required to evaluate the effectiveness of the intervention for eliciting clinically-important and sustainable weight loss in this population.

Bone turnover markers as determinants of bone density and fracture in men with distal forearm fractures: the pathogenesis examined in the Mr F study.

The pathogenesis for low-trauma wrist fractures in men is not fully understood. This study found that these men had evidence of significantly higher bone turnover compared with control subjects. Bone turnover markers were negative predictors of bone mineral density and were a predictor of fracture. INTRODUCTION: Men with distal forearm fractures have reduced bone density, an increased risk of osteoporosis and of further fractures. The aim of this study was to investigate whether or not men with distal forearm fractures had evidence of altered bone turnover activity. METHODS: Fifty eight men with low-trauma distal forearm fracture and 58 age-matched healthy control subjects were recruited. All subjects underwent a DXA scan of the forearm, both hips, and lumbar spine, biochemical investigations, and health questionnaires. Measurements of beta crosslaps (ßCTX), procollagen type I N-terminal propeptide (PINP), sclerostin, Dickkopf-1 (Dkk1), and fibroblast growth factor 23 (FGF 23) were made. RESULTS: Men with fracture had significantly higher PINP than controls at 39.2 ng/ml (SD 19.5) versus 33.4 ng/ml (SD13.1) (p<0.001). They also had significantly higher ßCTX at 0.45 ng/ml (SD 0.21) versus 0.37 ng/ml (SD 0.17) (p= 0.037). Fracture subjects had significantly lower aBMD and PINP was a negative predictor of aBMD at the total hip and ßCTX a negative predictor of forearm aBMD. Sclerostin was a positive predictor of aBMD at the lumbar spine and hip sites. Sex hormone binding globulin (SHBG) at 37nmol/L (SD 15.0) was lower in fracture cohort compared to 47.9 nmol/L (SD 19.2) (p=0.001) in control. Multiple regression revealed that the best model for prediction of fracture included SHBG, P1NP, and ultra-distal forearm aBMD. The likelihood of distal forearm fracture was decreased by 5.1% for each nmol/L increase in SHBH and by 1.4% for every mg/cm2 increase in ultra-distal forearm aBMD, but increased by 6.1 % for every ng/ml increase in P1NP. Men in the highest quartile of PINP had a significantly greater likelihood of distal forearm fracture than those in the lowest quartile. CONCLUSION: The fracture group had significantly higher PINP and ßCTX compared with the control group, and these markers were negative predictors of aBMD at the total hip and forearm sites, respectively. Sclerostin was a positive predictor of the variance of spinal and hip aBMD. Likelihood of forearm fracture was best predicted by a combination of SHBG, PINP, and ultra-distal forearm aBMD. Findings of such cross-sectional data should be treated with caution, as longitudinal studies would be required to confirm or refute them.

Histamine, mast cell tryptase and post-exercise hypotension in healthy and collapsed marathon runners.

PURPOSE: Heat stress exacerbates post-exercise hypotension (PEH) and cardiovascular disturbances from elevated body temperature may contribute to exertion-related incapacity. Mast cell degranulation and muscle mass are possible modifiers, though these hypotheses lack practical evidence. This study had three aims: (1) to characterise pre-post-responses in histamine and mast cell tryptase (MCT), (2) to investigate relationships between whole body muscle mass (WBMM) and changes in blood pressure post-marathon, (3) to identify any differences in incapacitated runners. METHODS: 24 recreational runners were recruited and successfully completed the 2019 Brighton Marathon (COMPLETION). WBMM was measured at baseline. A further eight participants were recruited from incapacitated runners (COLLAPSE). Histamine, MCT, blood pressure, heart rate, body temperature and echocardiographic measures were taken before and after exercise (COMPLETION) and upon incapacitation (COLLAPSE). RESULTS: In completion, MCT increased by nearly 50% from baseline (p = 0.0049), whereas histamine and body temperature did not vary (p > 0.946). Systolic (SBP), diastolic (DBP) and mean (MAP) arterial blood pressures and systemic vascular resistance (SVR) declined (p < 0.019). WBMM negatively correlated with Δ SBP (r = - 0.43, p = 0.046). For collapse versus completion, there were significant elevations in MCT (1.77 ± 0.25 µg/L vs 1.18 ± 0.43 µg/L, p = 0.001) and body temperature (39.8 ± 1.3 °C vs 36.2 ± 0.8 °C, p < 0.0001) with a non-significant rise in histamine (9.6 ± 17.9 µg/L vs 13.7 ± 33.9 µg/L, p = 0.107) and significantly lower MAP, DBP and SVR (p < 0.033). CONCLUSION: These data support the hypothesis that mast cell degranulation is a vasodilatory mechanism underlying PEH and exercise associated collapse. The magnitude of PEH is inversely proportional to the muscle mass and enhanced by concomitant body heating.

Infection, Survival, and Growth of Clavibacter nebraskensis on Crop, Weed, and Prairie Plant Species.

Clavibacter nebraskensis is the causal agent of Goss's leaf blight and wilt, an important disease of maize in the United States and Canada. The epidemiology and ecology of this bacterial pathogen are poorly understood. Infested maize residue is often considered to be the primary source of inoculum for maize; however, the potential for many other plant species to be infected and serve as inoculum sources is unknown. The goal of this study was to determine if C. nebraskensis could infect, survive, and grow on common weed, crop, and grass species. Seedling leaves of 18 plant species that grow in maize production areas in the United States were inoculated with this pathogen in a controlled environment and in the field. Lesion development, bacterial streaming, and pathogen population size on leaves were then determined and used as criteria to evaluate host-pathogen interactions. Woolly cupgrass (Eriochloa villosa) and the native prairie grasses big bluestem (Andropogon gerardii) and little bluestem (Schizachyrium scoparium) developed lesions and bacterial streaming, identifying them as hosts and susceptible to infection. To our knowledge, this is the first report of these grass species being hosts of C. nebraskensis. Ten other grass species, including wheat and oats, were identified as potential sustaining hosts that maintained epiphytic or endophytic pathogen populations >106 colony forming units per leaf sample but displayed no evidence of infection. Five broadleaf species tested were nonhosts based on the three criteria. This study suggests that multiple plant species support infection and growth of C. nebraskensis and further elucidates the ecology of this pathogen and the epidemiology of Goss's wilt.

Development of the Automated Primer Design Workflow Uniqprimer and Diagnostic Primers for the Broad-Host-Range Plant Pathogen Dickeya dianthicola.

Uniqprimer, a software pipeline developed in Python, was deployed as a user-friendly internet tool in Rice Galaxy for comparative genome analyses to design primer sets for PCRassays capable of detecting target bacterial taxa. The pipeline was trialed with Dickeya dianthicola, a destructive broad-host-range bacterial pathogen found in most potato-growing regions. Dickeya is a highly variable genus, and some primers available to detect this genus and species exhibit common diagnostic failures. Upon uploading a selection of target and nontarget genomes, six primer sets were rapidly identified with Uniqprimer, of which two were specific and sensitive when tested with D. dianthicola. The remaining four amplified a minority of the nontarget strains tested. The two promising candidate primer sets were trialed with DNA isolated from 116 field samples from across the United States that were previously submitted for testing. D. dianthicola was detected in 41 samples, demonstrating the applicability of our detection primers and suggesting widespread occurrence of D. dianthicola in North America.

Risk of pre-eclampsia in women taking metformin: a systematic review and meta-analysis.

AIMS: To perform meta-analyses of studies evaluating the risk of pre-eclampsia in high-risk insulin-resistant women taking metformin prior to, or during pregnancy. METHODS: A search was conducted of the Medline, EMBASE, Web of Science and Scopus databases. Both randomized controlled trials and prospective observational cohort studies of metformin treatment vs. placebo/control or insulin either prior to or during pregnancy were selected. The main outcome measure was the incidence of pre-eclampsia in each treatment group. RESULTS: Overall, in five randomized controlled trials comparing metformin treatment (n = 611) with placebo/control (n = 609), no difference in the risk of pre-eclampsia was found [combined/pooled risk ratio (RR), 0.86 (95% CI 0.33-2.26); P = 0.76; I2  = 66%]. Meta-analysis of four cohort studies again showed no significant effect [RR, 1.21 (95% CI 0.56-2.61); P = 0.62; I2  = 30%]. A meta-analysis of eight randomized controlled trials comparing metformin (n = 838) with insulin (n = 836), however, showed a reduced risk of pre-eclampsia with metformin [RR, 0.68 (95% CI 0.48-0.95); P = 0.02; I2  = 0%]. No heterogeneity was present in the metformin vs. insulin analysis of randomized controlled trials, whereas high levels of heterogeneity were present in studies comparing metformin with placebo/control. Pre-eclampsia was a secondary outcome in most of the studies. The mean weight gain from time of enrolment to delivery was lower in the metformin group (P = 0.05, metformin vs. placebo; P = 0.004, metformin vs. insulin). CONCLUSIONS: In studies randomizing pregnant women to glucose-lowering therapy, metformin was associated with lower gestational weight gain and a lower risk of pre-eclampsia compared with insulin.

Does regional loss of bone density explain low trauma distal forearm fractures in men (the Mr F study)?

The pathogenesis of low trauma wrist fractures in men is not fully understood. This study found that these men have lower bone mineral density at the forearm itself, as well as the hip and spine, and has shown that forearm bone mineral density is the best predictor of wrist fracture. INTRODUCTION: Men with distal forearm fractures have reduced bone density at the lumbar spine and hip sites, an increased risk of osteoporosis and a higher incidence of further fractures. The aim of this case-control study was to investigate whether or not there is a regional loss of bone mineral density (BMD) at the forearm between men with and without distal forearm fractures. METHODS: Sixty-one men with low trauma distal forearm fracture and 59 age-matched bone healthy control subjects were recruited. All subjects underwent a DXA scan of forearm, hip and spine, biochemical investigations, health questionnaires, SF-36v2 and Fracture Risk Assessment Tool (FRAX). The non-fractured arm was investigated in subjects with fracture and both forearms in control subjects. RESULTS: BMD was significantly lower at the ultradistal forearm in men with fracture compared to control subjects, in both the dominant (mean (SD) 0.386 g/cm2 (0.049) versus 0.436 g/cm2 (0.054), p < 0.001) and non-dominant arm (mean (SD) 0.387 g/cm2 (0.060) versus 0.432 g/cm2 (0.061), p = 0.001). Fracture subjects also had a significantly lower BMD at hip and spine sites compared with control subjects. Logistic regression analysis showed that the best predictor of forearm fracture was ultradistal forearm BMD (OR = 0.871 (0.805-0.943), p = 0.001), with the likelihood of fracture decreasing by 12.9% for every 0.01 g/cm2 increase in ultradistal forearm BMD. CONCLUSIONS: Men with low trauma distal forearm fracture have significantly lower regional BMD at the ultradistal forearm, which contributes to an increased forearm fracture risk. They also have generalised reduction in BMD, so that low trauma forearm fractures in men should be considered as indicator fractures for osteoporosis.

Co-morbid obsessive-compulsive disorder and depression: a Bayesian network approach.

BACKGROUND: Obsessive-compulsive disorder (OCD) is often co-morbid with depression. Using the methods of network analysis, we computed two networks that disclose the potentially causal relationships among symptoms of these two disorders in 408 adult patients with primary OCD and co-morbid depression symptoms. METHOD: We examined the relationship between the symptoms constituting these syndromes by computing a (regularized) partial correlation network via the graphical LASSO procedure, and a directed acyclic graph (DAG) via a Bayesian hill-climbing algorithm. RESULTS: The results suggest that the degree of interference and distress associated with obsessions, and the degree of interference associated with compulsions, are the chief drivers of co-morbidity. Moreover, activation of the depression cluster appears to occur solely through distress associated with obsessions activating sadness - a key symptom that 'bridges' the two syndromic clusters in the DAG. CONCLUSIONS: Bayesian analysis can expand the repertoire of network analytic approaches to psychopathology. We discuss clinical implications and limitations of our findings.

HrcU and HrpP are pathogenicity factors in the fire blight pathogen Erwinia amylovora required for the type III secretion of DspA/E.

BACKGROUND: Many Gram-negative bacterial pathogens mediate host-microbe interactions via utilization of the type III secretion (T3S) system. The T3S system is a complex molecular machine consisting of more than 20 proteins. Collectively, these proteins translocate effectors across extracellular space and into the host cytoplasm. Successful translocation requires timely synthesis and allocation of both structural and secreted T3S proteins. Based on amino acid conservation in animal pathogenic bacteria, HrcU and HrpP were examined for their roles in regulation of T3S hierarchy. RESULTS: Both HrcU and HrpP were shown to be required for disease development in an immature pear infection model and respective mutants were unable to induce a hypersensitive response in tobacco. Using in vitro western blot analyses, both proteins were also shown to be required for the secretion of DspA/E, a type 3 effector and an important pathogenicity factor. Via yeast-two hybridization (Y2H), HrpP and HrcU were revealed to exhibit protein-protein binding. Finally, all HrcU and HrpP phenotypes identified were shown to be dependent on a conserved amino acid motif in the cytoplasmic tail of HrcU. CONCLUSIONS: Collectively, these data demonstrate roles for HrcU and HrpP in regulating T3S and represent the first attempt in understanding T3S heirarchy in E. amylovora.

Dysphoria is a risk factor for depression in medically ill older people.

OBJECTIVES: Depression in older people is commonly under diagnosed and is associated with increased morbidity and mortality. Because older people currently occupy 65% of acute hospital beds, it is crucial for them to be properly assessed for depression to optimise their medical care. The aim of this study was to identify potential risk factors for depression in the medically ill in order to improve their inpatient care. METHODS: This was a 2-year observational study of consequent referrals to the Newcastle Liaison Team for Older Adults. Out of a total number of 1586 referred patients, 1197 were included in the final analysis of data. Information about their age, main medical history, cognitive impairment and use of antidepressants was collected. All subjects were screened for dementia, depression and delirium. Proportions were compared using the chi-squared test. Clinical depression as a binary variable was modelled using logistic regression. RESULTS: Higher risk for depression was associated with pain (odds ratio (OR) = 1.76; p = 0.033) and a previous history of depression (OR = 2.22; p < 0.001). Cognitive impairment (OR = 0.44, p < 0.001) and delirium (OR = 0.49; p < 0.001) decreased the likelihood for having depression. Subjective feelings of emptiness, being unhappy and depressed alone (R2 = 37.4%) and cognitive impairment (R2 = 39.5%) were the best multivariable model to explain depression in medically ill people. CONCLUSION: Dysphoric mood results in depression in older people with medical health problems. Copyright © 2016 John Wiley & Sons, Ltd.

PCR-Mediated Detection and Quantification of the Goss's Wilt Pathogen Clavibacter michiganensis subsp. nebraskensis Via a Novel Gene Target.

Goss's leaf blight and wilt of maize (corn) is a significant and reemerging disease caused by the bacterium Clavibacter michiganensis subsp. nebraskensis. Despite its importance, molecular tools for diagnosing and studying this disease remain limited. We report the identification of CMN_01184 as a novel gene target and its use in conventional PCR (cPCR) and SYBR green-based quantitative PCR (qPCR) assays for specific detection and quantification of C. michiganensis subsp. nebraskensis. The cPCR and qPCR assays based on primers targeting CMN_01184 specifically amplified only C. michiganensis subsp. nebraskensis among a diverse collection of 129 bacterial and fungal isolates, including multiple maize bacterial and fungal pathogens, environmental organisms from agricultural fields, and all known subspecies of C. michiganensis. Specificity of the assays for detection of only C. michiganensis subsp. nebraskensis was also validated with field samples of C. michiganensis subsp. nebraskensis-infected and uninfected maize leaves and C. michiganensis subsp. nebraskensis-infested and uninfested soil. Detection limits were determined at 30 and 3 ng of pure C. michiganensis subsp. nebraskensis DNA, and 100 and 10 CFU of C. michiganensis subsp. nebraskensis for the cPCR and qPCR assays, respectively. Infection of maize leaves by C. michiganensis subsp. nebraskensis was quantified from infected field samples and was standardized using an internal maize DNA control. These novel, specific, and sensitive PCR assays based on CMN_01184 are effective for diagnosis of Goss's wilt and for studies of the epidemiology and host-pathogen interactions of C. michiganensis subsp. nebraskensis.

Updated investigations of cancer excesses in individuals born or resident in the vicinity of Sellafield and Dounreay.

BACKGROUND: Earlier studies have shown raised risks of leukaemia and non-Hodgkin lymphoma in children, teenagers and young adults resident either at birth or diagnosis in Seascale. Some increases in cancer risk in these age groups have also been noted among those living around Dounreay. We aimed to update previous analyses relating to areas close to these nuclear installations by considering data from an additional 16 years of follow-up. METHODS: Cross-sectional analyses compared cancer incidence rates for 1963-2006 among those aged 0-24 years at diagnosis living in geographically specified areas around either Sellafield or Dounreay with general population rates. Cancer incidence for the period 1971-2006 among the cohort of Cumbrian births between 1950 and 2006 was compared to national incidence for 1971-2006 using person-years analysis. Cancer among those born in the postcode sector closest to Dounreay was compared with that among those born in the three adjoining postcode sectors. Analyses considered both cancer overall and ICD-O-3 defined diagnostic subgroups including leukaemia, central nervous system tumours and other malignancies. RESULTS: Apart from previously reported raised risks, no new significantly increased risks for cancer overall or any diagnostic subgroup were found among children or teenagers and young adults living around either nuclear installation. Individuals born close to the installations from 1950 to 2006 were not shown to be at any increased risk of cancer during the period 1971 to date. CONCLUSIONS: Analysis of recent data suggests that children, teenagers and young adults currently living close to Sellafield and Dounreay are not at an increased risk of developing cancer. Equally, there is no evidence of any increased cancer risk later in life among those resident in these areas at birth.

Survival from teenage and young adult cancer in Northern England, 1968-2008.

BACKGROUND: Although cancer is relatively rare in teenagers and young adults (TYAs) aged 15-24 years, it is a major cause of death in this age group. This study investigated survival trends in TYA cancer diagnosed in Northern England, 1968-2008. METHODS: Five-year survival was analyzed using Kaplan-Meier estimation for four successive time periods. Cox regression analysis was used to investigate associations with demographic factors. RESULTS: The study included 2,987 cases (1,634 males, 1,353 females). Five-year survival for all patients with cancer improved greatly from 46% in 1968-1977 to 84% in 1998-2008 (P < 0.001), for patients with leukemia from 2% to 71% (P < 0.001), lymphoma from 66% to 86% (P < 0.001), central nervous system tumors from 53% to 84% (P < 0.001), bone tumors from 29% to 72% (P < 0.001), germ cell tumors from 39% to 94% (P < 0.001), melanoma and skin cancer from 64% to 100% (P < 0.001), and carcinomas from 48% to 80% (P < 0.001). Cox analysis showed that for all patients with cancer, survival was better for females than males (HR = 0.83; 95% CI 0.74-0.94, P < 0.001), for patients aged 20-24 years compared with those aged 15-19 years (HR = 0.84; 95% CI 0.75-0.94, P = 0.002), but survival was worse for patients who resided in more deprived areas (HR = 1.06; 95% CI 1.01-1.11, P = 0.025). CONCLUSION: There have been large improvements in TYA cancer survival in Northern England over the last four decades. Future work should determine factors that could lead to even better survival, including possible links with delayed diagnosis.

Global small RNA chaperone Hfq and regulatory small RNAs are important virulence regulators in Erwinia amylovora.

Hfq is a global small RNA (sRNA) chaperone that interacts with Hfq-regulated sRNAs and functions in the posttranscriptional regulation of gene expression. In this work, we identified Hfq to be a virulence regulator in the Gram-negative fire blight pathogen Erwinia amylovora. Deletion of hfq in E. amylovora Ea1189 significantly reduced bacterial virulence in both immature pear fruits and apple shoots. Analysis of virulence determinants in strain Ea1189Δhfq showed that Hfq exerts pleiotropic regulation of amylovoran exopolysaccharide production, biofilm formation, motility, and the type III secretion system (T3SS). Further characterization of biofilm regulation by Hfq demonstrated that Hfq limits bacterial attachment to solid surfaces while promoting biofilm maturation. Characterization of T3SS regulation by Hfq revealed that Hfq positively regulates the translocation and secretion of the major type III effector DspE and negatively controls the secretion of the putative translocator HrpK and the type III effector Eop1. Lastly, 10 Hfq-regulated sRNAs were identified using a computational method, and two of these sRNAs, RprA and RyhA, were found to be required for the full virulence of E. amylovora.

Socioeconomic variation in survival from childhood leukaemia in northern England, 1968-2010.

BACKGROUND: Despite marked improvements in childhood leukaemia survival, 20% still die within 5 years of diagnosis. The aim of this study was to evaluate the relationship between socioeconomic status, as assessed by paternal occupation at birth, and survival from childhood leukaemia in children, using data from the Northern Region Young Persons Malignant Disease Registry. METHODS: All 1007 cases of leukaemia in children aged 0-14 years, diagnosed between 1968 and 2010 and registered with the Registry were studied. Paternal occupational social class at the time of the child's birth was obtained and analysed in relation to survival using Cox-proportional regression. RESULTS: Compared with the most advantaged group (I/II), those in the middle group (IIIN/M) had a 68% increased risk of death, while those in the least advantaged group (IV/V) had 86% higher risk for acute lymphoblastic leukaemia. While the survival advantage of children in class I/II was apparent from the time of diagnosis, survival for children in groups IIIN/M and IV/V were comparable until 3-4 years after diagnosis, when they began to minimally diverge. CONCLUSION: The existence of such socioeconomic disparities cannot be attributed to accessibility to health care in the United Kingdom. Further research into the likely factors underlying these disparities is required.

Management of complex colonic polyps in the English Bowel Cancer Screening Programme.

BACKGROUND: Large sessile or flat colonic polyps, defined as polyps at least 20 mm in size, are difficult to treat endoscopically and may harbour malignancy. The aim of this study was to describe their current management to provide insight into optimal management. METHODS: This retrospective observational study identified patients with large sessile or flat polyps detected in the English Bowel Cancer Screening Programme between 2006 and 2009. Initial therapeutic modality (surgical or endoscopic), subsequent management and outcomes were recorded. The main outcome measures analysed were: presence of malignancy, need for surgical treatment, complications, and residual or recurrent polyp at 12 months. RESULTS: In total, 557 large sessile or flat polyps with benign appearance or initial histology were identified in 557 patients. Some 436 (78.3 per cent) were initially managed endoscopically and 121 (21.7 per cent) were managed surgically from the outset. Seventy of those initially treated endoscopically subsequently required surgery owing to the presence of malignancy (19) or not being suitable for further endoscopic management (51). Residual or recurrent polyp was present at 12 months in 26 (6.0 per cent) of 436 patients managed endoscopically. There was wide variation between centres in the use of surgery as a primary therapy, ranging from 7 to 36 per cent. Endoscopic complications included bleeding in 13 patients (3.0 per cent) and perforation in two (0.5 per cent). CONCLUSION: Management of large sessile or flat colonic polyps is safe and effective in the English Bowel Cancer Screening Programme. Wide variation in the use of surgery suggests a need for standardized management algorithms. Presented to a meeting of the British Society of Gastroenterology, Birmingham, U.K., March 2011.

Longer mean colonoscopy withdrawal time is associated with increased adenoma detection: evidence from the Bowel Cancer Screening Programme in England.

BACKGROUND AND STUDY AIMS: Increasing colonoscopy withdrawal time (CWT) is thought to be associated with increasing adenoma detection rate (ADR). Current English guidelines recommend a minimum CWT of 6 minutes. It is known that in the Bowel Cancer Screening Programme (BCSP) in England there is wide variation in CWT. The aim of this observational study was to examine the relationship between CWT and ADR. PATIENTS AND METHODS: The study examined data from 31 088 colonoscopies by 147 screening program colonoscopists. Colonoscopists were grouped in four levels of mean CWT ( < 7, 7 - 8.9, 9 - 10.9, and ≥ 11 minutes). Univariable and multivariable analysis (binary logistic and negative binomial regression) were used to explore the relationship between CWT, ADR, mean number of adenomas and number of right-sided and advanced adenomas. RESULTS: In colonoscopists with a mean CWT < 7 minutes, the mean ADR was 42.5 % compared with 47.1 % in the ≥ 11-minute group (P < 0.001). The mean number of adenomas detected per procedure increased from 0.77 to 0.94, respectively (P < 0.001). The increase in adenoma detection was mainly of subcentimeter or proximal adenomas; there was no increase in the detection of advanced adenomas. Regression models showed an increase in ADR from 43 % to 46.5 % for mean CWT times ranging from 6 to 10 minutes. CONCLUSIONS: This study demonstrates that longer mean withdrawal times are associated with increasing adenoma detection, mainly of small or right-sided adenomas. However, beyond 10 minutes the increase in ADR is minimal. Mean withdrawal times longer than 6 minutes are not associated with increased detection of advanced adenomas. Withdrawal time remains an important quality metric of colonoscopy.