The Chelsea Critical Care Physical Assessment Tool (CPAx): validation of an innovative new tool to measure physical morbidity in the general adult critical care population; an observational proof-of-concept pilot study.

Objective To develop a scoring system to measure physical morbidity in critical care – the Chelsea Critical Care Physical Assessment Tool (CPAx). Method The development process was iterative involving content validity indices (CVI), a focus group and an observational study of 33 patients to test construct validity against the Medical Research Council score for muscle strength, peak cough flow, Australian Therapy Outcome Measures score, Glasgow Coma Scale score, Bloomsbury sedation score, Sequential Organ Failure Assessment score, Short Form 36 (SF-36) score, days of mechanical ventilation and inter-rater reliability. Participants Trauma and general critical care patients from two London teaching hospitals. Results Users of the CPAx felt that it possessed content validity, giving a final CVI of 1.00 (P < 0.05). Construct validation data showed moderate to strong significant correlations between the CPAx score and all secondary measures, apart from the mental component of the SF-36 which demonstrated weak correlation with the CPAx score (r = 0.024, P = 0.720). Reliability testing showed internal consistency of α = 0.798 and inter-rater reliability of κ = 0.988 (95% confidence interval 0.791 to 1.000) between five raters. Conclusion This pilot work supports proof of concept of the CPAx as a measure of physical morbidity in the critical care population, and is a cogent argument for further investigation of the scoring system

PaL Diagrams: A Linear Diagram-Based Visual Language

Linear diagrams have recently been shown to be more effective than Euler diagrams when used for set-based reasoning. However, unlike the growing corpus of knowledge about formal aspects of Euler and Venn diagrams, there has been no formalisation of linear diagrams. To fill this knowledge gap, we present and formalise Point and Line (PaL) diagrams, an extension of simple linear diagrams containing points, thus providing a formal foundation for an effective visual language.We prove that PaL diagrams are exactly as expressive as monadic first-order logic with equality, gaining, as a corollary, an equivalence with the Euler diagram extension called spider diagrams. The method of proof provides translations between PaL diagrams and sentences of monadic first-order logic

Logics for the Relational Syllogistic

The Aristotelian syllogistic cannot account for the validity of many inferences involving relational facts. In this paper, we investigate the prospects for providing a relational syllogistic. We identify several fragments based on (a) whether negation is permitted on all nouns, including those in the subject of a sentence; and (b) whether the subject noun phrase may contain a relative clause. The logics we present are extensions of the classical syllogistic, and we pay special attention to the question of whether reductio ad absurdum is needed. Thus our main goal is to derive results on the existence (or non-existence) of syllogistic proof systems for relational fragments. We also determine the computational complexity of all our fragments

Designing and implementing a COPD discharge care bundle

National surveys have revealed significant differences in patient outcomes following admission to hospital with acute exacerbation of COPD which are likely to be due to variations in care. We developed a care bundle, comprising a short list of evidence-based practices to be implemented prior to discharge for all patients admitted with this condition, based on a review of national guidelines and other relevant literature, expert opinion and patient consultation. Implementation was then piloted using action research methodologies with patient input. Actively involving staff was vital to ensure that the changes introduced were understood and the process followed. Implementation of a care bundle has the potential to produce a dramatic improvement in compliance with optimum health care practice

Non-invasive ventilation (NIV) as an aid to rehabilitation in acute respiratory disease

<p>Abstract</p> <p>Background</p> <p>Non-invasive ventilation (NIV) can increase exercise tolerance, reduce exercise induced desaturation and improve the outcome of pulmonary rehabilitation in patients with chronic respiratory disease. It is not known whether it can be applied to increase exercise capacity in patients admitted with non-hypercapnic acute exacerbations of COPD (AECOPD). We investigated the acceptability and feasibility of using NIV for this purpose.</p> <p>Methods</p> <p>On a single occasion, patients admitted with an acute exacerbation of chronic respiratory disease who were unable to cycle for five minutes at 20 watts attempted to cycle using NIV and their endurance time (T_lim) was recorded. To determine feasibility of this approach in clinical practice patients admitted with AECOPD were screened for participation in a trial of regular NIV assisted rehabilitation during their hospital admission.</p> <p>Results</p> <p>In 12 patients tested on a single occasion NIV increased T_limfrom 184(65) seconds to 331(229) seconds (p = 0.04) and patients desaturated less (median difference = 3.5%, p = 0.029). In the second study, 60 patients were admitted to hospital during a three month period of whom only 18(30)% were eligible to participate and of these patients, only four (7%) consented to participate.</p> <p>Conclusion</p> <p>NIV improves exercise tolerance in patients with acute exacerbations of chronic respiratory disease but the applicability of this approach in routine clinical practice may be limited.</p> <p>Trial registration</p> <p><url>http://www.controlled-trials.com/ISRCTN35692743</url></p

Solid phase peptide synthesis on a beaded cellulose support : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry at Massey University

The studies reported in this thesis describe the use of Perloza type MT beaded cellulose resin as an insoluble support for solid phase peptide synthesis (SPPS). The overall aim of the project was to develop a viable methodology for the synthesis of peptide-ligands directly onto Perloza for use as matrices for affinity chromatographic processes. A number of basic studies were carried out to define the solvent compatibility of Perloza. Perloza appeared to be swollen by a variety of solvents currently used for SPPS, in particular by dimethylformamide (DMF) and dioxane. It was found that Perloza could not be dried and then re-swollen to its original volume using water, DMF, dioxane, or several other solvents. Therefore, it was necessary that Perloza was maintained in a solvent-swollen state for all of the other studies reported in this thesis. Several methods for generation of amine-functionalised Perloza were investigated. The chosen method was reaction of Perloza with acrylonitrile in a 1:1 solution of dioxane:2% w/v NaOH to yield cyanoethyl Perloza. The level of cyanoethylation of the resin was controllable between the range of 0-3.7 mmole CN per gram of dry resin. The cyanoethyl Perloza was reduced with an excess of diborane in THF solution, either at room temperature or under reflux, to yield aminopropyl Perloza. Reduction yields varied from 52-100%. The peptide LAGV was synthesised onto aminopropyl Perloza using modified Boc SPPS methodology. It was found that protic Boc cleavage reagents gave cleavage of aminopropyl groups from functionalised Perloza. Therefore, a novel Boc cleavage reagent, boron trifluoride etherate in dioxane, was developed for Boc cleavage in all subsequent peptide syntheses using Perloza and the Boc methodology. C-terminal Boc-amino acids were anchored to α-bromoacetamido Perloza by nucleophilic displacement of bromine via the Boc-amino acid cesium salts. The procedure resulted in anchoring of the Boc-amino acids via an acid-stable but base-labile glycolamide linkage. Two test peptides, LAGV, and Leu-enkephalin (sequence: YGGFL), were synthesised on Perloza using a semimanual LKB Biolynx 4175 continuous flow peptide synthesiser. The peptides were cleaved using dilute NaOH solution. The tyrosine hydroxyl of Leu-enkephalin was protected as its benzyl ether, which was cleaved by catalytic hydrogenation prior to HPLC purification. The peptides were obtained in satisfactory yield after purification by HPLC. Several unsuccessful attempts were made to synthesise the Acyl Carrier Protein 65-74 sequence (VQAAIDYING) using Perloza, the glycolamide linkage, and Boc chemistry. The glycolamide linker was also investigated for use with Perloza and Fmoc chemistry. Leu-enkephalin was synthesised using Fmoc chemistry. The tBu ether protecting the side chain hydroxyl of the tyrosine was cleaved using 95% TFA while the peptide was left anchored to the Perloza. The peptide was then cleaved using the lithium salt of βME in THF. The cleavage yield of the peptide was low, about 32%. In addition, it was found that the Perloza was difficult to filter after the treatment with TFA, that is, its flow properties had been impaired. Leu-enkephalin with the side chain hydroxyl of the tyrosine protected as a tBu ether was obtained by cleavage of the peptide with LiβME in THF. This provided preliminary evidence that side-chain protected peptides (for further use in fragment syntheses) could be obtained using the glycolamide linker with Perloza. The Fmoc SPPS methodology was also investigated for use with Perloza. Fmoc-amino acids were anchored to aminopropyl Perloza via the 4-hydroxy-methylphenoxyacetyl (HMPA) linker using the preformed Fmoc-amino acyl-4-oxymethylphenoxyacetic acid 2,4-dichlorophenyl esters. All 20 Fmoc-amino acids were anchored to Perloza at substitution levels suitable for SPPS (up to 0.76 mmole amino acid per g of dry resin). The amide linker compound p-[(R,S)-α-(9H-fluoren-9-yl)-methoxyformamido-2,4-dimethoxy-benzyl]-phenoxyacetic acid was coupled to aminopropyl Perloza for syntheses of peptide amides. Both a semimanual continuous flow (LKB Biolynx 4175) and automated batchwise peptide synthesiser (ABI 430A) were used to carry out peptide syntheses. Little difference was seen in the quality of crude peptides derived from the two synthesisers. TFA solutions containing scavengers were used to cleave all peptides. It was found in all cases that treatment of peptide-Perloza with TFA seriously degraded the properties of the resin, in some cases the resin dissolved into the TFA. The peptides were purified by HPLC. Several peptides (LHRH, ACTH 4-11, Angiotensins I and II) were synthesised on Perloza and compared with authentic samples obtained from a commercial source. In addition, a number of non-standard peptides, up to 21 amino acids in length, were successfully synthesised using the Fmoc SPPS methodology with Perloza. Two peptide-ligands were synthesised directly onto aminopropyl Perloza for testing of the peptide-Perloza conjugates as affinity matrices for biomolecule purifications. VdLPFFVdL-amidopropyl Perloza was synthesised using Boc chemistry. The peptide-Perloza was tested for binding of chymosin. It was found that chymosin would not bind to the peptide-Perloza conjugate without succinylation of the N-terminal amine group. The peptide-Perloza was used for the affinity isolation of recombinant chymosin from a solution containing a number of contaminant fungal proteins. The side chain protected peptide luteinising hormone-releasing hormone (protected LHRH, sequence pGlu-His(Trt)-Trp-Ser(tBu)-Tyr(tBu)-Gly-Leu-Arg(Mtr)-Pro-Gly-NH2) was synthesised directly onto aminopropyl Perloza. The side chain protecting groups (Trt, 2X tBu, Mtr) were cleaved quantitatively using an acidic reagent (80% DCM, 16% TFA, 1% TMSBR, 1% thioanisole, 1% EDT, 1% m-cresol), with insignificant cleavage of the peptide-ligand from the support, and no apparent impairment of the flow properties of the Perloza. The peptide-resin was then employed for the affinity isolation of antibodies to LHRH derived from a sheep immunised with LHRH conjugated to BSA. A search of the literature revealed that, in many cases, the C-terminal glycine-amide of LHRH was required for binding antibodies to LHRH. A novel means for directed immobilisation of peptide-ligands to α-bromo-acetamido Perloza was conceived and investigated in order to direct the C-terminal glycine amide into the aqueous phase. A cysteine-containing analogue of LHRH (Ac-Cys-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) was synthesised using amide linker Perloza and Fmoc chemistry. The LHRH analogue was purified by HPLC. Reaction of a 1.3-1.5X excess of the LHRH analogue with α-bromoacetamido Perloza in 0.1M NaHCO3 solution resulted in anchoring of the peptide to the support via a stable thioether bond. The coupling reaction went in greater than 95% yield in 1-2 hours. The peptide-Perloza conjugate was used for the successful isolation of antibodies to LHRH