The application of a time delay model to chemical engineering operations

Methods are developed for describing flow and transport phenomena in chemical process equipment in terms of random time delays that are undergone by material or energy elements in passing through the process. It is shown how these methods may be applied to typical chemical engineering processes including exchange processes in packed beds, distillation and multiple reactions in complex flow regimes. A new mixing concept, dynamic dispersion, is defined which may be used to account, in a formal way, for the disparity that sometimes exists between the behaviour of a process in the steady state and predictions based on the axial dispersion concept

The Stereodivergent Formation of 2,6-cis and 2,6-trans-Tetrahydropyrans: Experimental and Computational Investigation of the Mechanism of a Thioester Oxy-Michael Cyclization

The origins of the stereodivergence in the thioester oxy-Michael cyclization for the formation of 4-hydroxy-2,6-cis- or 2,6-trans-substituted tetrahydropyran rings under different conditions was investigated both computationally and experimentally. Synthetic studies showed that the 4-hydroxyl group was essential for stereodivergence. When the 4-hydroxyl group was present, TBAF-mediated conditions gave the 2,6-trans-tetrahydropyran and trifluoroacetic acid-mediated conditions gave the 2,6-cis-tetrahydropyran. This stereodivergence vanished when the hydroxyl group was removed or protected. Computational studies revealed that: (i) the trifluoroacetic acid catalysed formation of 2,6-cis-tetrahydropyrans was mediated by a trifluoroacetate-hydroxonium bridge and proceeded via a chair-like transition state; (ii) the TBAF-mediated formation of 2,6-trans-tetrahydropyrans proceeded via a boat-like transition state, where the 4-hydroxyl group formed a crucial hydrogen bond to the cyclizing alkoxide; (iii) both reactions are under kinetic control. The utility of this stereodivergent approach for the formation of 4-hydroxy-2,6-substituted tetrahydropyran rings has been demonstrated by the total syntheses of the anti-osteoporotic natural products diospongin A and

Reduction of catheter associated urinary tract infection (CAUTI) rates organization-wide begins in the ED

Poster presentation Session B presented Monday, September 30,11:30 am-12:30 pm Purpose: Background: In quarter four of 2017, 40% of Catheter Associated Urinary Tract Infections (CAUTI) were attributed to the insertion of the indwelling urinary catheter in the Emergency Department (ED). The common practice of urgent insertion of indwelling catheters led to poor technique and increased CAUTI. Sterile procedures should be done in a sterile environment and not rushed. The creation of institutional guidelines for indwelling urinary catheter insertion coupled with physician and nurse champions led to a reduction in unnecessary utilization. Changes in practice, improved technique and reducing use of indwelling catheters in the ED lowered the incidence of CAUTI in our hospital by 70%. Design: This was a quality improvment project. Setting: 911 receiving ED at Providence Saint Joseph Medical Center with specialty center capabilities for STEMI and Stroke. Participants/Subjects: Participants included all admitted patients from the ED who did not have a diagnosis of obstruction and/or therapeutic hypothermia. Methods: A Plan Do Study Act (PDSA) process was used for this quality improvement project. The infection prevention team met with ED leaders and discussed the necessity of “Foley Free ED. Baseline data over two quarters was tracked. Data points established, the total number of foleys inserted, appropriateness of indication and presence of orders were analyzed. It was observed that indwelling urinary catheters were often inserted without orders or appropriate indications. The action plan included ED specific indwelling urinary catheter insertion guidelines and implementation of alternative external devices. An interprofessional staff education plan was implemented with weekly chart reviews to evaluate adherence of new guidelines. Results/Outcomes: A two Tailed t-Test for the pre and post implementation period resulted with a p-value of 0.04. This indicates that the difference between the insertion rates are statistically significant. As a result of the “Foley Free ED†project, insertion rates have been reduced by 66%. CAUTI rates, per the National Healthcare Safety Network definition, declined from 3.17 in June 2018, to 0.96 in November 2018, which is a 70% reduction. Implications: Implementation of “Foley Free ED†is associated with reduction of CAUTI cases attributed to indwelling urinary catheters inserted in the ED. Based on project findings, the authors suggest implementing practice guidelines that restrict indwelling urinary catheter insertion in the ED only to those undergoing therapeutic hypothermia or with urinary obstruction/retention

Identification of compounds acting as negative allosteric modulators of the LPA ₁ receptor

The Lysophosphatidic Acid 1 Receptor (LPA1 receptor) has been linked to the initiation and progression of a variety of poorly treated fibrotic conditions. Several compounds that have been described as LPA1 receptor antagonists have progressed into clinical trials: 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]phenyl}phenyl)cyclopropane-1-carboxylic acid (BMS-986202) and 2-{4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzamido}-2,3-dihydro-1H-indene-2-carboxylic acid (SAR-100842). We considered that as LPA1 receptor function is involved in many normal physiological processes, inhibition of specific signalling pathways associated with fibrosis may be therapeutically advantageous. We compared the binding and functional effects of a novel compound; 4-({(Cyclopropylmethyl)[4-(2-fluorophenoxy)benzoyl]amino}methyl}benzoic acid (TAK-615) with BMS-986202 and SAR-100842. Back-scattering interferometry (BSI) was used to show that the apparent affinity of TAK-615 was enhanced in the presence of LPA. The binding signal for BMS-986202 was not detected in the presence of LPA suggesting competition but interestingly the apparent affinity of SAR-100842 was also enhanced in the presence of LPA. Only BMS-986202 was able to fully inhibit the response to LPA in calcium mobilisation, β-arrestin, cAMP, GTPγS and RhoA functional assays. TAK-615 and SAR-100842 showed different inhibitory profiles in the same functional assays. Further binding studies indicated that TAK-615 is not competitive with either SAR-100842 or BMS-986202, suggesting a different site of binding. The results generated with this set of experiments demonstrate that TAK-615 acts as a negative allosteric modulator (NAM) of the LPA1 receptor. Surprisingly we find that SAR-100842 also behaves like a NAM. BMS-986202 on the other hand behaves like an orthosteric antagonist.</p

Synthesis of the pedamide fragment of onnamide F

This thesis is concerned with the synthesis of two key fragments of onnamide F, a marine natural product isolated from the sponge Trachycladus laevispirulifer. Onnamide F has been shown to be a particularly potent inhibitor of fungal growth and the development of parasitic larvae. Onnamide F has not been synthesised previously, but synthetic approaches to the structurally related natural products pederin, mycalamides A and B, theopederin D, onnamide A and psymberin / irciniastatin A are discussed in Chapter 1. Chapter 2 details a racemic synthesis of the central tetrahydropyran fragment of onnamide F. The realisation of an asymmetric synthesis of the pedamide fragment based on the aforementioned synthesis is described in Chapter 3. Details of key ring- hydroxylation, expansion and cyclisation reactions are presented, including discussion of the influence of internal steric and kinetic factors on their stereochemical course. Optimisation of the key cyclisation reaction that delivers the required functionalised THP system proved challenging and required modification of the original synthetic target. This work, and synthesis of a key conjugated diene fragment are discussed in Chapter 4. Some initial research towards a formal synthesis of the related natural product psymberin is described in Chapter 5.</p