UK clinical experience up to 52 weeks with linaclotide for irritable bowel syndrome with constipation

Background: Linaclotide, a guanylate cyclase C agonist, has been shown in clinical trials to improve symptoms of irritable bowel syndrome with constipation (IBS-C). Here we report data from a real-world study of linaclotide in the UK. Methods: This 1-year, multicentre, prospective, observational study in the UK enrolled patients aged 18 years and over initiating linaclotide for IBS-C. The primary assessment was change from baseline in IBS Symptom Severity Scale (IBS-SSS) score at 12 weeks, assessed in patients with paired baseline and 12-week data. Change from baseline in IBS-SSS score at 52 weeks was a secondary assessment. Adverse events were recorded. Results: In total, 202 patients were enrolled: 185 (91.6%) were female, median age was 44.9 years (range 18.1–77.2) and 84 (41.6%) reported baseline laxative use. Mean (standard deviation) baseline IBS-SSS score was 339 (92), with most patients (n = 129; 66.8%) classified as having severe disease (score ⩾300). In patients with paired data, there was a significant mean (95% confidence interval) decrease in IBS-SSS score from baseline to 12 weeks [−77.0 (−96.3, −57.7); p < 0.001; n = 124] and baseline to 52 weeks [−70.7 (−95.0, −46.5); p < 0.001; n = 76]. Overall, 174 adverse events were reported in 77 (38.1%) patients, most commonly diarrhoea (n = 54; 26.7%), abdominal pain (n = 21; 10.4%) and abdominal distension (n = 13; 6.4%). Conclusion: Linaclotide significantly improved IBS-SSS score at 12 and 52 weeks. These results provide insights into outcomes with linaclotide treatment over 1 year in patients with IBS-C in real-world clinical practice

The Influence of Dormitory Architecture On Resident Behavior

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66943/2/10.1177_001391657300500402.pd

Formalizing undefinedness arising in calculus

Abstract. Undefined terms are commonplace in mathematics, particularly in calculus. The traditional approach to undefinedness in mathematical practice is to treat undefined terms as legitimate, nondenoting terms that can be components of meaningful statements. The traditional approach enables statements about partial functions and undefined terms to be stated very concisely. Unfortunately, the traditional approach cannot be easily employed in a standard logic in which all functions are total and all terms are defined, but it can be directly formalized in a standard logic if the logic is modified slightly to admit undefined terms and statements about definedness. This paper demonstrates this by defining a version of simple type theory called Simple Type Theory with Undefinedness (sttwu) and then formalizing in sttwu examples of undefinedness arising in calculus. The examples are taken from M. Spivak’s well-known textbook Calculus.

An Infrastructure for Intertheory Reasoning

The little theories method, in which mathematical reasoning is distributed across a network of theories, is a powerful technique for describing and analyzing complex systems. This paper presents an infrastructure for intertheory reasoning that can support applications of the little theories method. The infrastructure includes machinery to store theories and theory interpretations, to store known theorems of a theory with the theory, and to make denitions in a theory by extending the theory &quot;in place&quot;. The infrastructure is an extension of the intertheory infrastructure employed in the imps Interactive Mathematical Proof System

The metabolism of deuterated analogues of chlorambucil by the rat

The antitumour agent chlorambucil 4[4-bis(2-chloroethyl)aminophenyl]butyric acid is converted by β-oxidation in vivo into phenylacetic mustard 2[4-bis(2-chloroethyl)aminophenyl]acetic acid. This process may be disadvantageous from a therapeutic viewpoint since the metabolite has half the therapeutic index of the parent drug against the Walker 256 carcinoma in rats. In seeking to retard β-oxidation, selectively deuterated analogues have been synthesised and administered to rats. Plasma levels of phenylacetic mustard after giving chlorambucil-β-d2 were lower than those given by unlabelled drug, but the therapeutic activity was not significantly altered by deuteration. A dehydro derivative of chlorambucil was detected as an intermediate in the β-oxidation pathway. The isotopic compositions of this metabolite, and of recovered chlorambucil, were measured in plasma samples taken after giving labelled chlorambucil (α-d2 and β-d2 variants) to rats. Deuterium was almost totally lost from the α-d2 form and from its metabolite after 30 min and partially lost in 10 min. The β-d2 variant and its dehydro-derivative retained the label. Possible mechanisms for deuteration loss are discussed. The design of novel analogues, based on these metabolic studies, is proposed. © 1979

Terminating Tableaux for the Basic Fragment of Simple Type Theory

We consider the basic fragment of simple type theory, which restricts equations to base types and disallows lambda abstractions and quantifiers. We show that this fragment has the finite model property and that satisfiability can be decided with a terminating tableau system. Both results are with respect to standard models.

Genotoxic damage in mine workers exposed to diesel exhaust, and the effects of glutathione transferase genotypes

This study was performed in an Estonian shale-oil mine with the purpose to develop and apply a number of biomarkers for occupational diesel-exhaust exposure monitoring. Increased breathing-zone exposures to exhaust from operators of diesel-powered trucks in the mine was confirmed in the environmental monitoring part of the study, showing a 7.5-fold higher exposure to particle-associated 1-nitropyrene (1-NP) in 50 underground workers compared with 42 surface workers [P.T.J. Scheepers, D. Coggon, L.E. Knudsen, R. Anzion, H. Autrup, S. Bogovski, R.P. Bos, D. Dahmann, P. Farmer, E.A. Martin, V. Micka, V. Muzyka, H.-G. Neumann, J. Poole, A. Schmidt-Ott, F. Seiler, J. Volf, I. Zwirner-Baier, Biomarkers for occupational diesel exhaust exposure monitoring (BIOMODEM)-a study in underground mining, Toxicol. Lett. 134 (2002) 305-317; P.T.J. Scheepers, V. Micka, V. Muzyka, R. Anzion, D. Dahmann, J. Poole, R.P. Bos, Exposure to dust and particle-associated 1-nitropyrene of drivers of diesel-powered equipment in underground mining, Ann. Occp. Hyg. 47 (2003) 379-388]. Analysis of DNA damage by the Comet assay on frozen blood samples was performed on the total study group and showed significantly higher levels (p=0.003) in underground workers (smokers) driving diesel-powered excavation machines (median 155 on a scale from 0 to 400, among 47 persons), compared with surface workers who smoked (median of 90, among 46 persons). The level of DNA damage in underground smokers was significantly higher (p=0.04) than in non-smokers. Samples from 2 of the 3 sampling weeks had significantly lower DNA damage compared with the third week, probably due to timely processing and freezing. These samples also showed significant differences (p&lt;0.001) between underground workers (median 145, among 41 persons) and surface workers (median 60, among 30 persons). An HPLC method was developed for the analysis of (32)P-postlabelled 1-NP-DNA-adducts, and was applied to a sub-sample of 20 workers. No significant differences between surface and underground workers were found in this sub-sample with respect to the minor, unidentified adducts that had similar chromatographic properties to 1-NP adducts, and smoking did not have any effect on adduct levels. No significant effects of the genotypes of GSTM1, GSTP1 and GSTT1 on DNA-adducts and on DNA damage as measured by the Comet assay were found in the total study group. The study confirms an increased level of DNA damage in workers exposed to exhaust from truck-driving in the mine. However, the results of the environmental and biological monitoring of 1-NP did not correlate, suggesting that inhalation exposure to diesel exhaust is not reflected by an increase in 1-NP-DNA-adduct levels and/or that factors other than occupational exposure to diesel exhaust are primary determinants of these DNA-adduct levels