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Promiscuity, or selectivity on a spectrum, is an encoded feature in biomolecular anion recognition. To unravel the molecular drivers of promiscuous anion recognition, we have employed a comprehensive approach – spanning experiment and theory – with the Staphylococcus carnosus nitrate regulatory element A (ScNreA) as a model. Thermodynamic analysis reveals that ScNreA complexation with native nitrate and nitrite or non-native iodide is an exothermic process. Further deconvolution of the association and dissociation kinetics for each anion reveals that the release event can be limiting, in turn, giving rise to the observed selectivity: nitrate > iodide > nitrite. These conclusions are supplemented with molecular dynamics simulations that capture an entry and exit pathway coupled to subtle global protein motions unique to each anion. Taken together, our data point to how structural plasticity of the binding pocket controls the relative promiscuity of ScNreA to guarantee physiological nitrate sensing. Proteins can exhibit a significant degree of anion selectivity, but the factors underlying promiscuous anion coordination remain underexplored. Here, the authors study the Staphylococcus carnosus nitrate regulatory element A (ScNreA) as a model system and show that ScNreA complexation to nitrate, nitrite or iodide is an exothermic process controlled by the structural plasticity of the binding pocket.

ObjectiveThe English Bowel Cancer Screening Programme (BCSP) recommends 3 yearly colonoscopy surveillance for patients at intermediate risk of colorectal cancer (CRC) postpolypectomy (those with three to four small adenomas or one ≥10 mm). We investigated whether faecal immunochemical tests (FITs) could reduce surveillance burden on patients and endoscopy services.DesignIntermediate-risk patients (60–72 years) recommended 3 yearly surveillance were recruited within the BCSP (January 2012–December 2013). FITs were offered at 1, 2 and 3 years postpolypectomy. Invitees consenting and returning a year 1 FIT were included. Participants testing positive (haemoglobin ≥40 µg/g) at years one or two were offered colonoscopy early; all others were offered colonoscopy at 3 years. Diagnostic accuracy for CRC and advanced adenomas (AAs) was estimated considering multiple tests and thresholds. We calculated incremental costs per additional AA and CRC detected by colonoscopy versus FIT surveillance.Results74% (5938/8009) of invitees were included in our study having participated at year 1. Of these, 97% returned FITs at years 2 and 3. Three-year cumulative positivity was 13% at the 40 µg/g haemoglobin threshold and 29% at 10 µg/g. 29 participants were diagnosed with CRC and 446 with AAs. Three-year programme sensitivities for CRC and AAs were, respectively, 59% and 33% at 40 µg/g, and 72% and 57% at 10 µg/g. Incremental costs per additional AA and CRC detected by colonoscopy versus FIT (40 µg/g) surveillance were £7354 and £180 778, respectively.ConclusionsReplacing 3 yearly colonoscopy surveillance in intermediate-risk patients with annual FIT could reduce colonoscopies by 71%, significantly cut costs but could miss 30%–40% of CRCs and 40%–70% of AAs.Trial registration number ISRCTN18040196; Results.

Existing and emerging methods in computational mechanics are rarely validated against problems with an unknown outcome. For this reason, Sandia National Laboratories, in partnership with US National Science Foundation and Naval Surface Warfare Center Carderock Division, launched a computational challenge in mid-summer, 2012. Researchers and engineers were invited to predict crack initiation and propagation in a simple but novel geometry fabricated from a common off-the-shelf commercial engineering alloy. The goal of this international Sandia Fracture Challenge was to benchmark the capabilities for the prediction of deformation and damage evolution associated with ductile tearing in structural metals, including physics models, computational methods, and numerical implementations currently available in the computational fracture community. Thirteen teams participated, reporting blind predictions for the outcome of the Challenge. The simulations and experiments were performed independently and kept confidential. The methods for fracture prediction taken by the thirteen teams ranged from very simple engineering calculations to complicated multiscale simulations. The wide variation in modeling results showed a striking lack of consistency across research groups in addressing problems of ductile fracture. While some methods were more successful than others, it is clear that the problem of ductile fracture prediction continues to be challenging. Specific areas of deficiency have been identified through this effort. Also, the effort has underscored the need for additional blind prediction-based assessments.

Ductile failure of structural metals is relevant to a wide range of engineering scenarios. Computational methods are employed to anticipate the critical conditions of failure, yet they sometimes provide inaccurate and misleading predictions. Challenge scenarios, such as the one presented in the current work, provide an opportunity to assess the blind, quantitative predictive ability of simulation methods against a previously unseen failure problem. Rather than evaluate the predictions of a single simulation approach, the Sandia Fracture Challenge relies on numerous volunteer teams with expertise in computational mechanics to apply a broad range of computational methods, numerical algorithms, and constitutive models to the challenge. This exercise is intended to evaluate the state of health of technologies available for failure prediction. In the first Sandia Fracture Challenge, a wide range of issues were raised in ductile failure modeling, including a lack of consistency in failure models, the importance of shear calibration data, and difficulties in quantifying the uncertainty of prediction [see Boyce et al. (Int J Fract 186:5–68, 2014 ) for details of these observations]. This second Sandia Fracture Challenge investigated the ductile rupture of a Ti–6Al–4V sheet under both quasi-static and modest-rate dynamic loading (failure in ∼ 0.1 s). Like the previous challenge, the sheet had an unusual arrangement of notches and holes that added geometric complexity and fostered a competition between tensile- and shear-dominated failure modes. The teams were asked to predict the fracture path and quantitative far-field failure metrics such as the peak force and displacement to cause crack initiation. Fourteen teams contributed blind predictions, and the experimental outcomes were quantified in three independent test labs. Additional shortcomings were revealed in this second challenge such as inconsistency in the application of appropriate boundary conditions, need for a thermomechanical treatment of the heat generation in the dynamic loading condition, and further difficulties in model calibration based on limited real-world engineering data. As with the prior challenge, this work not only documents the ‘state-of-the-art’ in computational failure prediction of ductile tearing scenarios, but also provides a detailed dataset for non-blind assessment of alternative methods.

The phenotypic expression in familial adenomatous polyposis (FAP) is variable. This study compares the phenotype of 27 patients with an identical 5 base pair (bp) deletion at codon 1309 with a group of 61 matched patients with FAP where knowledge of specific mutations is not available and with seven other different mutations in 24 subjects. Patients with the codon 1309 deletion have significantly more colorectal polyps at the time of colectomy than age and sex matched FAP controls (p = 0.0001). The median number of polyps in colectomy specimens of patients with the deletion at codon 1309 was 4000 (interquartile (IQ) range 3000-4875), compared with 600 (IQ range 488-1400) in the matched controls. Mutations at codon 1323, 1407, and 233 were also associated with large numbers of polyps. Desmoid disease and extracolonic cancers were more common with the mutation at codon 1309 (p = 0.003). In conclusion, there may be a correlation between a specific germline mutation and the number of large bowel polyps. There is residual heterogeneity in phenotypic expression, however, and this may result from the influence of other genes, specific environmental factors or chance.

Introduction: Stiff-person Syndrome (SPS) is a rare autoimmune central nervous system disorder characterized by rigidity of the trunk and proximal limb muscles due to continuous co-contraction of agonists and antagonists with superimposed intermittent and often disabling spasms of the involved musculature. Dyspnea was assessed on each subject via a vertical Visual Analogue Scale assessed on the day of study visit (VAS1day) and over the preceding two weeks (VAS2weeks), and by the University of San Diego Shortness Of Breath Questionnaire (UCSD-SOBQ).

IntroductionColonoscopic surveillance for colorectal cancer (CRC) is widely practiced; however, there remains a lack of evidence to determine appropriate surveillance intervals for individuals at intermediate risk (IR) of CRC. Due to the considerable strain on endoscopic resources and serious cost implications, it is vital to optimise surveillance strategies to ensure colonoscopy is targeted at those who will benefit most. This study examines the frequency of surveillance in patients with intermediate grade (IG) adenomas, aiming to assess whether there is significant heterogeneity in the detection of advanced neoplasia within this group, according to baseline findings and surveillance interval length.MethodsA retrospective cohort design was used in a secondary care setting. 18 UK hospitals were selected based on the availability of electronic patient data suitable for automatic extraction. Endoscopy reports containing Systematised Nomenclature of Medicine codes or words relating to adenomas were identified and linked to corresponding pathology records. These were extracted from hospital databases before being pseudo-anonymised, formatted and uploaded onto an APEX database to be interpreted and coded. Patients were excluded from the analysis if they had no IG adenomas, no baseline colonoscopy, any missing exam dates or conditions affecting CRC risk. Baseline and follow-up visits, and polyp characteristics, were defined using a series of rules developed by the study team. Outcome measures used were advanced adenomas (AA) and CRC; information on these was obtained using follow-up data from external sources, in addition to the hospital data.Analysis of risk of AA and CRC at each follow-up visit, according to baseline findings and interval length, will be performed through the use of descriptive statistics and logistic regression.Approval was obtained from the National Research Ethics Service, Caldicott Guardians and the National Information Governance Board. As it was not feasible to seek patient consent, patient confidentiality was ensured through pseudo-anonymisation of data.ResultsEndoscopy and pathology data from over 200,000 patients was collected and coded, and a large bespoke database was created to store this data. A total of 11,995 IR patients with a baseline colonoscopy were identified for analysis, 4,694 of whom have at least one follow-up visit.ConclusionAnalysis of the data is currently in progress. When completed, later this year, conclusions will be drawn on the optimal surveillance intervals for IR patients. The database will also act as a unique resource for further studies involving patients at both low and high risk, and for examining the association between serrated lesions and proximal CRC.Disclosure of InterestNone Declared.

Introduction Colonoscopic surveillance for colorectal cancer (CRC) is widely practiced; however, there remains a lack of evidence to determine appropriate surveillance intervals for individuals at intermediate risk (IR) of CRC. Due to the considerable strain on endoscopic resources and serious cost implications, it is vital to optimise surveillance strategies to ensure colonoscopy is targeted at those who will benefit most. This study examines the frequency of surveillance in patients with intermediate grade (IG) adenomas, aiming to assess whether there is significant heterogeneity in the detection of advanced neoplasia within this group, according to baseline findings and surveillance interval length. Methods A retrospective cohort design was used in a secondary care setting. 18 UK hospitals were selected based on the availability of electronic patient data suitable for automatic extraction. Endoscopy reports containing Systematised Nomenclature of Medicine codes or words relating to adenomas were identified and linked to corresponding pathology records. These were extracted from hospital databases before being pseudo-anonymised, formatted and uploaded onto an APEX database to be interpreted and coded. Patients were excluded from the analysis if they had no IG adenomas, no baseline colonoscopy, any missing exam dates or conditions affecting CRC risk. Baseline and follow-up visits, and polyp characteristics, were defined using a series of rules developed by the study team. Outcome measures used were advanced adenomas (AA) and CRC; information on these was obtained using follow-up data from external sources, in addition to the hospital data. Analysis of risk of AA and CRC at each follow-up visit, according to baseline findings and interval length, will be performed through the use of descriptive statistics and logistic regression. Approval was obtained from the National Research Ethics Service, Caldicott Guardians and the National Information Governance Board. As it was not feasible to seek patient consent, patient confidentiality was ensured through pseudo-anonymisation of data. Results Endoscopy and pathology data from over 200,000 patients was collected and coded, and a large bespoke database was created to store this data. A total of 11,995 IR patients with a baseline colonoscopy were identified for analysis, 4,694 of whom have at least one follow-up visit. Conclusion Analysis of the data is currently in progress. When completed, later this year, conclusions will be drawn on the optimal surveillance intervals for IR patients. The database will also act as a unique resource for further studies involving patients at both low and high risk, and for examining the association between serrated lesions and proximal CRC. Disclosure of Interest None Declared.

Introduction Background UK and USA surveillance guidelines recommend 3-yearly surveillance for intermediate and higher-risk groups, respectively. To date, no study has examined surveillance needs in this group, which comprises nearly half of patients with adenomas. Aims and objective(s) To identify the optimum frequency of surveillance and assess whether there is substantial heterogeneity in risk; to examine the risks of cancer and advanced adenomas (AA). Method Design and Setting Retrospective, multi-centre cohort study, involving a hospitals dataset drawn from 17 UK NHS hospitals (n = 11,944), and three pooled screening cohorts (n = 2,353). Subjects Patients with intermediate-grade adenoma (s) defined as having 3-4 small adenomas (<10 mm), or 1-2 adenomas, at least one of which is large (≥10 mm). Primary outcomes AA and colorectal cancer (CRC) detected at the first and second follow-up visits, and CRC incidence after baseline and first follow-up. Results Among 4,608 patients with follow-up in the hospital dataset, an increase in interval length was associated with a significant increased odds of AA and CRC at the first follow-up (p < 0.001). Of 1,635 patients attending a second follow-up, a significant association was also found between interval and odds of advanced neoplasia at the second follow-up (p = 0.026). Among 11,944 patients, 168 CRCs occurred during 81,442 person-years of observation time after baseline (206 per 100,000 pyrs, 95% CI 177-240). A single surveillance visit conferred a considerable reduction in risk of CRC after baseline (p = 0.0001). Other independent predictors of CRC were used to devise higher (HIR) and lower (LIR) intermediate risk subgroups, between which there was substantial heterogeneity in risk. A single surveillance exam lowered risk in the HIR subgroup (n = 9,265); however the benefit of surveillance in the LIR (n = 2,679) was unclear. 1,828 intermediate risk patients with at least one follow-up in the pooled screening cohorts were younger, on average, than the hospital cohort. No association was found between findings at follow-up and interval, however, there was evidence of the benefit of surveillance and the LIR and HIR subgroups derived from the hospital dataset were discriminant of CRC risk in the screening participants. Conclusion A surveillance interval of three to four years seems suitable for the majority of intermediate-risk patients. Surveillance lowers future risk of CRC in intermediate risk patients; however there was heterogeneity in risk and surveillance needs, which suggested that a single follow-up may suffice in certain intermediate-risk patients. Disclosure of interest None Declared.

APC is often cited as a prime example of a tumor suppressor gene. Truncating germline and somatic mutations (or, infrequently, allelic loss) occur in tumors in FAP (familial adenomatous polyposis). Most sporadic colorectal cancers also have two APC mutations 1 . Clues from attenuated polyposis 2 , 3 , 4 , missense germline variants with mild disease 5 , 6 and the somatic mutation cluster region (codons 1,250–1,450) 1 , 7 , 8 indicate, however, that APC mutations might not result in simple loss of protein function. We have found that FAP patients with germline APC mutations within a small region (codons 1,194–1,392 at most) mainly show allelic loss in their colorectal adenomas, in contrast to other FAP patients, whose 'second hits' tend to occur by truncating mutations in the mutation cluster region. Our results indicate that different APC mutations provide cells with different selective advantages, with mutations close to codon 1,300 providing the greatest advantage. Allelic loss is selected strongly in cells with one mutation near codon 1,300. A different germline–somatic APC mutation association exists in FAP desmoids. APC is not, therefore, a classical tumor suppressor. Our findings also indicate a new mechanism for disease severity: if a broader spectrum of mutations is selected in tumors, the somatic mutation rate is effectively higher and more tumors grow.