DNA methylation of ESR-1 and N-33 in colorectal mucosa of patients with Ulcerative Colitis (UC)

Introduction: Epigenetic marking such as DNA methylation influence gene transcription and chromosomal stability and may also be affected by environmental exposures. Few studies exist on alteration in DNA methylation profiles (genomic and gene specific methylation) in patients with Ulcerative Colitis (UC) and none assessing its relationship with lifestyle exposures. Aims & Methods: To assess genomic methylation and promoter methylation of the ESR-1 (oestrogen receptor - 1) and N-33 (tumour suppressor candidate-3) genes in the macroscopically normal mucosa of UC patients as well as to investigate effects of anthropometric and lifestyle exposures on DNA methylation. Sixty eight subjects were recruited (24 UC and 44 age and sex matched controls). Colorectal mucosal biopsies were obtained and DNA was extracted. Genomic DNA methylation was quantified using the tritium-labelled cytosine extension assay (3[H] dCTP) whilst gene specific methylation was quantified using the COBRA method. Results: The methylation level of both ESR-1 and N-33 genes were significantly higher in UC subjects compared with controls (7.9% vs 5.9%; p = 0.015 and 66% vs 9.3%; p < 0.001 respectively). There was no detectable difference in global DNA methylation between patients with UC and age and sex matched controls. No associations between indices of DNA methylation and anthropometric measures or smoking patterns were detected. Conclusions: For the first time, we have shown increased methylation in the promoter regions of the putative tumour suppressor gene N-33 in macroscopically normal mucosa of patients with UC. In addition, we have confirmed that methylation of ESR-1 promoter is higher in UC patients compared with age and sex matched controls. These findings suggests that, inactivation through methylation of the putative tumour suppressor genes N-33 and ESR-1, may not be associated with colorectal carcinogenesis in UC

Preventing and lessening exacerbations of asthma in school-age children associated with a new term (PLEASANT) : Study protocol for a cluster randomised control trial

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedBackground: Within the UK, during September, there is a pronounced increase in the number of unscheduled medical contacts by school-aged children (4-16 years) with asthma. It is thought that that this might be caused by the return back to school after the summer holidays, suddenly mixing with other children again and picking up viruses which could affect their asthma. There is also a drop in the number of prescriptions administered in August. It is possible therefore that children might not be taking their medication as they should during the summer contributing to them becoming ill when they return to school. It is hoped that a simple intervention from the GP to parents of children with asthma at the start of the summer holiday period, highlighting the importance of maintaining asthma medication can help prevent increased asthma exacerbation, and unscheduled NHS appointments, following return to school in September.Methods/design: PLEASANT is a cluster randomised trial. A total of 140 General Practices (GPs) will be recruited into the trial; 70 GPs randomised to the intervention and 70 control practices of "usual care" An average practice is expected to have approximately 100 children (aged 4-16 with a diagnosis of asthma) hence observational data will be collected on around 14000 children over a 24-month period. The Clinical Practice Research Datalink will collect all data required for the study which includes diagnostic, prescription and referral data.Discussion: The trial will assess whether the intervention can reduce exacerbation of asthma and unscheduled medical contacts in school-aged children associated with the return to school after the summer holidays. It has the potential to benefit the health and quality of life of children with asthma while also improving the effectiveness of NHS services by reducing NHS use in one of the busiest months of the year. An exploratory health economic analysis will gauge any cost saving associated with the intervention and subsequent impacts on quality of life. If results for the intervention are positive it is hoped that this could be adopted as part of routine care management of childhood asthma in general practice. Trial registration: Current controlled trials: ISRCTN03000938 (assigned 19/10/12) http://www.controlled-trials.com/ISRCTN03000938/.UKCRN ID: 13572.Peer reviewe

Comparative costs and activity from a sample of UK clinical trials units

BackgroundThe costs of medical research are a concern. Clinical Trials Units (CTU) need to better understand reasonable and legitimate variations in the costs of activities.MethodsRepresentatives of ten CTUs and two grant-awarding bodies pooled their experiences in discussions over a year-and-a-half. Five of the CTUs provided estimates of, and written justification for, costs associated with CTU activities required to implement an identical protocol. The protocol described a 5.5 year non-pharmacological RCT conducted at 20 centres. Direct and indirect costs, the number of Full Time Equivalents (FTEs) and the FTEs attracting overheads were compared and qualitative methods (unstructured interviews and thematic analysis) were used to interpret the results. Four members of the group (funding-body representatives or award panel members) reviewed the justification statements for transparency and information content. Separately, 163 activities common to trials were assigned to roles used by nine CTUs; the consistency of role delineation was assessed by Cohen's κ.ResultsMedian full economic cost of CTU activities was £769,637 (range: £661,112 to £1,383,323). Indirect costs varied considerably, accounting for between 15% and 59% (median 35%) of the full economic cost of the grant. Excluding one CTU which used external statisticians, the total number of FTEs ranged from 2.0 to 3.0; total FTEs attracting overheads ranged from 0.3 to 2.0. Variation in directly incurred staff costs depended on whether CTUs: supported particular roles from core funding rather than grants; opted not to cost certain activities into the grant; assigned clerical or data management tasks to research or administrative staff; employed extensive on-site monitoring strategies (also the main source of variation in non-staff costs). Funders preferred written justifications of costs that described both FTEs and indicative tasks for funded roles, with itemised non-staff costs. Consistency in role delineation was fair(κ=0.21-0.40) for statisticians / data managers and poor for other roles (κ&lt;0.20).ConclusionsSome variation in costs is due to factors outside the control of CTUs, such as access to core funding and levels of indirect costs levied by host institutions. Research is needed on strategies to control costs appropriately, especially the implementation of risk-based monitoring strategies

Haemorrhoidal artery ligation versus rubber band ligation for the management of symptomatic second-degree and third-degree haemorrhoids (HubBLe): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Optimum surgical intervention for low-grade haemorrhoids is unknown. Haemorrhoidal artery ligation (HAL) has been proposed as an efficacious, safe therapy while rubber band ligation (RBL) is a commonly used outpatient treatment. We compared recurrence after HAL versus RBL in patients with grade II-III haemorrhoids. METHODS: This multicentre, open-label, parallel group, randomised controlled trial included patients from 17 acute UK NHS trusts. We screened patients aged 18 years or older presenting with grade II-III haemorrhoids. We excluded patients who had previously received any haemorrhoid surgery, more than one injection treatment for haemorrhoids, or more than one RBL procedure within 3 years before recruitment. Eligible patients were randomly assigned (in a 1:1 ratio) to either RBL or HAL with Doppler. Randomisation was computer-generated and stratified by centre with blocks of random sizes. Allocation concealment was achieved using a web-based system. The study was open-label with no masking of participants, clinicians, or research staff. The primary outcome was recurrence at 1 year, derived from the patient's self-reported assessment in combination with resource use from their general practitioner and hospital records. Recurrence was analysed in patients who had undergone one of the interventions and been followed up for at least 1 year. This study is registered with the ISRCTN registry, ISRCTN41394716. FINDINGS: From Sept 9, 2012, to May 6, 2014, of 969 patients screened, 185 were randomly assigned to the HAL group and 187 to the RBL group. Of these participants, 337 had primary outcome data (176 in the RBL group and 161 in the HAL group). At 1 year post-procedure, 87 (49%) of 176 patients in the RBL group and 48 (30%) of 161 patients in the HAL group had haemorrhoid recurrence (adjusted odds ratio [aOR] 2·23, 95% CI 1·42-3·51; p=0·0005). The main reason for this difference was the number of extra procedures required to achieve improvement (57 [32%] participants in the RBL group and 23 [14%] participants in the HAL group had a subsequent procedure for haemorrhoids). The mean pain 1 day after procedure was 3·4 (SD 2·8) in the RBL group and 4·6 (2·8) in the HAL group (difference -1·2, 95% CI -1·8 to -0·5; p=0·0002); at day 7 the scores were 1·6 (2·3) in the RBL group and 3·1 (2·4) in the HAL group (difference -1·5, -2·0 to -1·0; p<0·0001). Pain scores did not differ between groups at 21 days and 6 weeks. 15 individuals reported serious adverse events requiring hospital admission. One patient in the RBL group had a pre-existing rectal tumour. Of the remaining 14 serious adverse events, 12 (7%) were among participants treated with HAL and two (1%) were in those treated with RBL. Six patients had pain (one treated with RBL, five treated with HAL), three had bleeding not requiring transfusion (one treated with RBL, two treated with HAL), two in the HAL group had urinary retention, two in the HAL group had vasovagal upset, and one in the HAL group had possible sepsis (treated with antibiotics). INTERPRETATION: Although recurrence after HAL was lower than a single RBL, HAL was more painful than RBL. The difference in recurrence was due to the need for repeat bandings in the RBL group. Patients (and health commissioners) might prefer such a course of RBL to the more invasive HAL. FUNDING: NIHR Health Technology Assessment programme

Classification and stratification in pilonidal sinus disease: findings from the PITSTOP cohort

Aim: Research in pilonidal disease faces several challenges, one of which is consistent and useful disease classification. The International Pilonidal Society (IPS) proposed a four‐part classification in 2017. The aim of this work was to assess the validity and reliability of this tool using data from the PITSTOP cohort study. Method: Face validity was assessed by mapping the items/domains in the IPS tool against tools identified through a systematic review. Key concepts were defined as those appearing in more than two‐thirds of published tools. Concurrent and predictive validity were assessed by comparing key patient‐reported outcome measures between groups at baseline and at clinic visit. The outcomes of interest were health utility, Cardiff Wound Impact Questionnaire (CWIQ) and pain score between groups. Significance was set at p = 0.05 a priori. Interrater reliability was assessed using images captured during the PITSTOP cohort. Ninety images were assessed by six raters (two experts, two general surgeons and two trainees), and classified into IPS type. Interrater reliability was assessed using the unweighted kappa and unweighted Gwet's AC1 statistics. Results: For face validity items represented in the IPS were common to other classification systems. Concurrent and predictive validity assessment showed differences in health utility and pain between groups at baseline, and for some treatment groups at follow‐up. Assessors agreed the same classification in 38% of participants [chance‐corrected kappa 0.52 (95% CI 0.42–0.61), Gwet's AC1 0.63 (95% CI 0.56–0.69)]. Conclusion: The IPS classification demonstrates key aspects of reliability and validity that would support its implementation

Research and practice priorities in pilonidal sinus disease: a consensus from the PITSTOP study

Aim: Pilonidal sinus disease is a common condition treated by colorectal surgeons. There is a lack of literature in the field to guide optimal management of this condition. As part of the PITSTOP study, we aimed to identify policy and research priorities to provide direction to the field. Method: Patients and surgeons were invited to participate. A ‘So what, now what’ exercise was conducted, informed by data from PITSTOP. This generated statements for research and practice priorities. A three‐round online Delphi study was conducted, ranking statements based on policy and research separately. Statements were rated 1 (not important) to 9 (important). Statements that were rated 7–9 by more than 70% of participants were entered into the consensus meeting. Personalized voting feedback was shown between rounds. A face‐to‐face meeting was held to discuss statements, and participants were asked to rank statements using a weighted choice vote. Results: Twenty‐two people participated in the focus group, generating 14 research and 19 policy statements. Statements were voted on by 56 participants in round 1, 53 in round 2 and 51 in round 3. A total of 15 policy statements and 19 research statements were discussed in the consensus round. Key policy statements addressed treatment strategies and intensity, surgeon training opportunities, need for classification and the impact of treatment on return to work. Research recommendations included design of future trials, methodology considerations and research questions. Conclusion: This study has identified research and policy priorities in pilonidal sinus disease which are relevant to patients and clinicians. These should inform practice and future research

Malnutrition, nutritional interventions and clinical outcomes of patients with acute small bowel obstruction : results from a national, multicentre, prospective audit

Objective: The aim of this study was to assess the nutritional status of patients presenting with small bowel obstruction (SBO), along with associated nutritional interventions and clinical outcomes. Design: Prospective cohort study. Setting: 131 UK hospitals with acute surgical services. Participants: 2069 adult patients with a diagnosis of SBO were included in this study. The mean age was 67.0 years and 54.7% were female. Primary and secondary outcome measures: Primary outcome was in-hospital mortality. Secondary outcomes recorded included: major complications (composite of in-hospital mortality, reoperation, unplanned intensive care admission and 30-day readmission), complications arising from surgery (anastomotic leak, wound dehiscence), infection (pneumonia, surgical site infection, intra-abdominal infection, urinary tract infection, venous catheter infection), cardiac complications, venous thromboembolism and delirium. Results: Postoperative adhesions were the most common cause of SBO (49.1%). Early surgery (<24 hours postadmission) took place in 30.0% of patients, 22.0% underwent delayed operation and 47.9% were managed non-operatively. Malnutrition as stratified by Nutritional Risk Index was common, with 35.7% at moderate risk and 5.7% at severe risk of malnutrition. Dietitian review occurred in just 36.4% and 55.9% of the moderate and severe risk groups. In the low risk group, 30.3% received nutritional intervention compared with 40.7% in moderate risk group and 62.7% in severe risk group. In comparison to the low risk group, patients who were at severe or moderate risk of malnutrition had 4.2 and 2.4 times higher unadjusted risk of in-hospital mortality, respectively. Propensity-matched analysis found no difference in outcomes based on use or timing of parenteral nutrition. Conclusions: Malnutrition on admission is associated with worse outcomes in patients with SBO, and marked variation in management of malnutrition was observed. Future trials should focus on identifying effective and cost-effective nutritional interventions in SBO

Is group cognitive behaviour therapy for postnatal depression evidence-based practice? A systematic review

Background: There is evidence that psychological therapies including cognitive behaviour therapy (CBT) may be effective in reducing postnatal depression (PND) when offered to individuals. In clinical practice, this is also implemented in a group therapy format, which, although not recommended in guidelines, is seen as a cost-effective alternative. To consider the extent to which group methods can be seen as evidence-based, we systematically review and synthesise the evidence for the efficacy of group CBT compared to currently used packages of care for women with PND, and we discuss further factors which may contribute to clinician confidence in implementing an intervention. Methods: Seventeen electronic databases were searched. All full papers were read by two reviewers and a third reviewer was consulted in the event of a disagreement on inclusion. Selected studies were quality assessed, using the Cochrane Risk of Bias Tool, were data extracted by two reviewers using a standardised data extraction form and statistically synthesised where appropriate using the fixed-effect inverse-variance method. Results: Seven studies met the inclusion criteria. Meta-analyses showed group CBT to be effective in reducing depression compared to routine primary care, usual care or waiting list groups. A pooled effect size of d = 0.57 (95% CI 0.34 to 0.80, p < 0.001) was observed at 10–13 weeks post-randomisation, reducing to d = 0.28 (95% CI 0.03 to 0.53, p = 0.025) at 6 months. The non-randomised comparisons against waiting list controls at 10–13 weeks was associated with a larger effect size of d = 0.94 (95% CI 0.42 to 1.47, p < 0.001). However due to the limitations of the available data, such as ill-specified definitions of the CBT component of the group programmes, these results should be interpreted with caution. Conclusions: Although the evidence available is limited, group CBT was shown to be effective. We argue, therefore, that there is sufficient evidence to implement group CBT, conditional upon routinely collected outcomes being benchmarked against those obtained in trials of individual CBT, and with other important factors such as patient preference, clinical experience, and information from the local context taken into account when making the treatment decision

Cytoplasmic p21(WAF1/CIP1 )expression is correlated with HER-2/ neu in breast cancer and is an independent predictor of prognosis

BACKGROUND: HER-2 (c-erbB2/Neu) predicts the prognosis of and may influence treatment responses in breast cancer. HER-2 activity induces the cytoplasmic location of p21(WAFI/CIPI )in cell culture, accompanied by resistance to apoptosis. p21(WAFI/CIPI )is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest in association with nuclear localisation of p21(WAFI/CIPI). We previously showed that higher levels of cytoplasmic p21(WAFI/CIPI )in breast cancers predicted reduced survival at 5 years. The present study examined HER-2 and p21(WAFI/CIPI )expression in a series of breast cancers with up to 9 years of follow-up, to evaluate whether in vitro findings were related to clinical data and the effect on outcome. METHODS: The CB11 anti-HER2 monoclonal antibody and the DAKO Envision Plus system were used to evaluate HER-2 expression in 73 patients. p21(WAFI/CIPI )staining was performed as described previously using the mouse monoclonal antibody Ab-1 (Calbiochem, Cambridge, MA, USA). RESULTS: HER-2 was evaluable in 67 patients and was expressed in 19% of cases, predicting reduced overall survival (P = 0.02) and reduced relapse-free survival (P = 0.004; Cox regression model). HER-2-positive tumours showed proportionately higher cytoplasmic p21(WAFI/CIPI )staining using an intensity distribution score (median, 95) compared with HER-2-negative cancers (median, 47) (P = 0.005). There was a much weaker association between nuclear p21(WAFI/CIPI )and HER-2 expression (P = 0.05), suggesting an inverse relationship between nuclear p21(WAF1/CIP1 )and HER-2. CONCLUSION: This study highlights a new pathway by which HER-2 may modify cancer behaviour. HER-2 as a predictor of poor prognosis may partly relate to its ability to influence the relocalisation of p21(WAFI/CIPI )from the nucleus to the cytoplasm, resulting in a loss of p21(WAFI/CIPI)tumour suppressor functions. Cytoplasmic p21(WAFI/CIPI )may be a surrogate marker of functional HER-2 in vivo