Objectives To assess the variation in risk-adjusted 30-day postoperative mortality for patients with colorectal cancer between hospital trusts within the English NHS. Design Retrospective cross-sectional population-based study of data extracted from the National Cancer Data Repository. Setting All providers of major colorectal cancer surgery within the English NHS. Participants All 160 920 individuals who underwent major resection for colorectal cancer diagnosed between 1998 and 2006 in the English NHS. Main outcome measures National patterns of 30-day postoperative mortality were examined and logistic binary regression was used to study factors associated with death within 30 days of surgery. Funnel plots were used to show variation between trusts in risk-adjusted mortality.Results Overall 30-day mortality was 6.7% but decreased over time from 6.8% in 1998 to 5.8% in 2006. The largest reduction in mortality was seen in 2005 and 2006. Postoperative mortality increased with age (15.0% (95% CI 14.1% to 15.9%) for those aged >80 years), comorbidity (24.2% (95% CI 22.0% to 26.5%) for those with a Charlson comorbidity score $3), stage of disease (9.9% (95% CI 9.3% to 10.6%) for patients with Dukes' D disease), socioeconomic deprivation (7.8% (95% CI 7.2% to 8.4%) for residents of the most deprived quintile) and operative urgency (14.9% (95% CI 14.2% to 15.7%) for patients undergoing emergency resection). Risk-adjusted control charts showed that one trust had consistently significantly better outcomes and three had significantly worse outcomes than the population mean. Conclusions Significant variation in 30-day postoperative mortality following major colorectal cancer surgery existed between NHS hospitals in England throughout the period 1998e2006. Understanding the underlying causes of this variation between surgical providers will make it possible to identify and spread best practice, improve outcomes and, ultimately, reduce 30-day postoperative mortality following colorectal cancer surgery.

Background: Rising levels of obesity coupled with the limited success of currently available weight control methods highlight the need for investigation of novel approaches to obesity treatment. This study aims to determine the effectiveness and cost-effectiveness of an Internet-based resource for obesity management.

SUMMARY Microsatellite repeat expansions in DNA produce pathogenic RNA species that cause dominantly inherited diseases such as myotonic dystrophy type 1 and 2 (DM1/2), Huntington’s disease, and C9orf72-linked amyotrophic lateral sclerosis (C9-ALS). Means to target these repetitive RNAs are required for diagnostic and therapeutic purposes. Here, we describe the development of a programmable CRISPR system capable of specifically visualizing and eliminating these toxic RNAs. We observe specific targeting and efficient elimination of micro-satellite repeat expansion RNAs both when exogenously expressed and in patient cells. Importantly, RNA-targeting Cas9 (RCas9) reverses hallmark features of disease including elimination of RNA foci among all conditions studied (DM1, DM2, C9-ALS, polyglutamine diseases), reduction of polyglutamine protein products, relocalization of repeat-bound proteins to resemble healthy controls, and efficient reversal of DM1-associated splicing abnormalities in patient myotubes. Finally, we report a truncated RCas9 system compatible with adeno-associated viral packaging. This effort highlights the potential of RCas9 for human therapeutics.

A B S T R A C T PurposeThis population-level study was conducted to define the health-related quality of life (HRQL) of individuals living with and beyond colorectal cancer (CRC) and to identify factors associated with poor health outcomes. Patients and MethodsAll individuals diagnosed with CRC in England in 2010 and 2011 who were alive 12 to 36 months after diagnosis were sent a questionnaire. This included questions related to treatment, disease status, other long-term conditions (LTCs), generic HRQL (EuroQol-5D), and cancer-specific outcomes (Functional Assessment of Cancer Therapy and Social Difficulties Inventory items). ResultsThe response rate was 63.3% (21,802 of 34,467 patients). One or more generic health problems were reported by 65% of respondents, with 10% of patients reporting problems in all five domains. The reporting of problems was higher than in the general population and was most marked in those age less than 55 years. Certain subgroups reported a higher number of problems, notably those with one or more other LTCs, those with active or recurrent disease, those with a stoma, and those at the extremes of the age range (Ͻ 55 and Ͼ 85 years). Of respondents without a stoma, 16.3% reported no bowel control. Reversal of a stoma resulted in fewer severe bowel problems but more moderate problems than those who had never had a stoma. A quarter of rectal cancer respondents (25.1%) reported difficulties with sexual matters (compared with 11.2% of colon cancer respondents). ConclusionThis study demonstrates the success of a national patient-reported outcomes survey. The results have the potential to support system-wide improvement in health outcomes through the identification of particular challenges faced by individuals after treatment for CRC. J Clin

ObjectivePost-colonoscopy colorectal cancer (PCCRC) is a key quality indicator of colonoscopy. This study compares methods for defining PCCRC rates, proposes a new method of calculating them and quantifies them across the English National Health Service (NHS).DesignThis retrospective observational population-based study involved all individuals with a first primary diagnosis of colorectal cancer made between 2001 and 2010 and treated in the English NHS. Previously published methods for deriving PCCRC rates were applied to the linked routine health data for this population to investigate the effect on the rate. A new method, based on the year of the colonoscopy rather than colorectal cancer diagnosis, was then used to calculate PCCRC rates.ResultsOf 297 956 individuals diagnosed with colorectal cancer, a total of 94 648 underwent a colonoscopy in the 3 years prior to their diagnosis. The application of the published methods and exclusion criteria to the dataset produced significantly different PCCRC rates from 2.5% to 7.7%. The new method demonstrates that PCCRC rates within 3 years of colonoscopy (without exclusions) decreased in the English NHS over 8 years, falling from 10.6% to 7.3% for colonoscopies performed in 2001 and 2007 respectively.ConclusionsThe method used to determine PCCRC rates significantly affects findings with potential to substantially underestimate rates. To enable international benchmarking there needs to be a standardised method for defining PCCRC. This study proposes a new methodology using colonoscopy as a denominator and between 2001 and 2007 this method indicated an 8.6% PCCRC rate across the English NHS. It also demonstrated PCCRC rates have fallen over time.

Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTG exp ) disorder caused by expression of CUG exp RNAs. These mutant RNAs alter the activities of RNA processing factors, including MBNL proteins, leading to re-expression of fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, the molecular basis of congenital DM (CDM) is unknown. Here, we test the hypothesis that disruption of developmentally regulated RNA alternative processing pathways contributes to CDM disease. We identify prominent alternative splicing and polyadenylation abnormalities in infant CDM muscle, and, although most are also misregulated in adult-onset DM1, dysregulation is significantly more severe in CDM. Furthermore, analysis of alternative splicing during human myogenesis reveals that CDM-relevant exons undergo prenatal RNA isoform transitions and are predicted to be disrupted by CUG exp -associated mechanisms in utero. To test this possibility and the contribution of MBNLs to CDM pathogenesis, we generated mouse Mbnl double (Mbnl1; Mbnl2) and triple (Mbnl1; Mbnl2; Mbnl3) muscle-specific knockout models that recapitulate the congenital myopathy, gene expression, and spliceopathy defects characteristic of CDM. This study demonstrates that RNA misprocessing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for cotranscriptional/post-transcriptional gene regulation during development.

Over the study period the use of APE decreased but statistically significant variation was observed in its application independently of case mix. Reducing this variation will remove inequalities, reduce colostomy rates, and improve outcomes in rectal cancer. Rates of APE use could be a national performance measure.

The rate of resection of liver metastases increased over the study period but varied significantly across the country. Patients who underwent liver resection had 5-year survival comparable to that of patients with stage III colorectal cancer.