Water-Based Dynamic Depsipeptide Chemistry: Building Block Recycling and Oligomer Distribution Control Using Hydration-Dehydration Cycles.

The high kinetic barrier to amide bond formation has historically placed narrow constraints on its utility in reversible chemistry applications. Slow kinetics has limited the use of amides for the generation of diverse combinatorial libraries and selection of target molecules. Current strategies for peptide-based dynamic chemistries require the use of nonpolar co-solvents or catalysts or the incorporation of functional groups that facilitate dynamic chemistry between peptides. In light of these limitations, we explored the use of depsipeptides: biorelevant copolymers of amino and hydroxy acids that would circumvent the challenges associated with dynamic peptide chemistry. Here, we describe a model system of N-(α-hydroxyacyl)-amino acid building blocks that reversibly polymerize to form depsipeptides when subjected to two-step evaporation-rehydration cycling under moderate conditions. The hydroxyl groups of these units allow for dynamic ester chemistry between short peptide segments through unmodified carboxyl termini. Selective recycling of building blocks is achieved by exploiting the differential hydrolytic lifetimes of depsipeptide amide and ester bonds, which we show are controllable by adjusting the solution pH, temperature, and time as well as the building blocks' side chains. We demonstrate that the polymerization and breakdown of the depsipeptides are facilitated by cyclic morpholinedione intermediates, and further show how structural properties dictate half-lives and product oligomer distributions using multifunctional building blocks. These results establish a cyclic mode of ester-based reversible depsipeptide formation that temporally separates the polymerization and depolymerization steps for the building blocks and may have implications for prebiotic polymer chemical evolution.

Evaluation of the ASSIGN open-source deterministic address-matching algorithm for allocating unique property reference numbers to general practitioner-recorded patient addresses.

INTRODUCTION: Linking places to people is a core element of the UK government's geospatial strategy. Matching patient addresses in electronic health records to their Unique Property Reference Numbers (UPRNs) enables spatial linkage for research, innovation and public benefit. Available algorithms are not transparent or evaluated for use with addresses recorded by health care providers. OBJECTIVES: To describe and quality assure the open-source deterministic ASSIGN address-matching algorithm applied to general practitioner-recorded patient addresses. METHODS: Best practice standards were used to report the ASSIGN algorithm match rate, sensitivity and positive predictive value using gold-standard datasets from London and Wales. We applied the ASSIGN algorithm to the recorded addresses of a sample of 1,757,018 patients registered with all general practices in north east London. We examined bias in match results for the study population using multivariable analyses to estimate the likelihood of an address-matched UPRN by demographic, registration, and organisational variables. RESULTS: We found a 99.5% and 99.6% match rate with high sensitivity (0.999,0.998) and positive predictive value (0.996,0.998) for the Welsh and London gold standard datasets respectively, and a 98.6% match rate for the study population.The 1.4% of the study population without a UPRN match were more likely to have changed registered address in the last 12 months (match rate: 95.4%), be from a Chinese ethnic background (95.5%), or registered with a general practice using the SystmOne clinical record system (94.4%). Conversely, people registered for more than 6.5 years with their general practitioner were more likely to have a match (99.4%) than those with shorter registration durations. CONCLUSIONS: ASSIGN is a highly accurate open-source address-matching algorithm with a high match rate and minimal biases when evaluated against a large sample of general practice-recorded patient addresses. ASSIGN has potential to be used in other address-based datasets including those with information relevant to the wider determinants of health.

Tracheostomy management in acute care facilities--a matter of teamwork.

AIM: Implement and evaluate an inter-disciplinary team approach to tracheostomy management in non-critical care. BACKGROUND: Trends towards early tracheostomy in intensive care units (ICU) have led to increased numbers of tracheostomy patients. Together with the push for earlier discharge from ICU, this poses challenges across disciplines and wards. Even though tracheostomy is performed across a range of patient groups, tracheostomy care is seen as the domain of specialist clinicians in critical care. It is crucial to ensure quality care regardless of the patient's destination after ICU. DESIGN: A mixed method evaluation incorporating quantitative and qualitative approaches. METHOD: Data collection included pre-implementation and postimplementation clinical audits and staff surveys and a postimplementation tracheostomy team focus group. Descriptive and inferential analysis was used to identify changes in clinical indicators and staff experiences. Focus group data were analysed using iterative processes of thematic analysis. RESULTS: Findings revealed significant reductions in mean hospital length of stay (LOS) for survivors from 50-27 days (p < 0.0001) and an increase in the number of tracheostomy patients transferred to non-critical care wards in the postgroup (p = 0.006). The number of wards accepting patients from ICU increased from 3-7 and there was increased staff knowledge, confidence and awareness of the team's role. CONCLUSION: The team approach has led to work practice and patient outcome improvements. Organisational acceptance of the team has led to more wards indicating willingness to accept tracheostomy patients. Improved communication has resulted in more timely referral and better patient outcomes. RELEVANCE TO CLINICAL PRACTICE: This study highlights the importance of inter-disciplinary teamwork in achieving effective patient outcomes and efficiencies. It offers a model of inter-disciplinary practice, supported by communication and data management that can be replicated across other patient groups.

Development of a microinstillation model of inhalation exposure to assess lung injury following exposure to toxic chemicals and nerve agents in Guinea pigs.

Respiratory disturbances due to chemical warfare nerve agents (CWNAs) are the starting point of mass casualty and the primary cause of death by these weapons of terror and mass destruction. However, very few studies have been implemented to assess respiratory toxicity and exacerbation induced by CWNAs, especially methylphosphonothioic acid S-(2-(bis(1-methylethyl)amino)ethyl)O-ethyl ester (VX). In this study, we developed a microinstillation technique of inhalation exposure to assess lung injury following exposure to CWNAs and toxic chemicals. Guinea pigs were gently intubated by placing a microcatheter into the trachea 1.5 to 2.0 cm centrally above the bifurcation. This location is crucial to deliver aerosolized agents uniformly to the lung's lobes. The placement of the tube is calculated by measuring the distance from the upper front teeth to the tracheal bifurcation, which is typically 8.5 cm for guinea pigs of equivalent size and a weight range of 250 g to 300 g. The catheter is capable of withstanding 100 psi pressure; the terminus has five peripheral holes to pump air that aerosolizes the nerve agent that is delivered in the central hole. The microcatheter is regulated by a central control system to deliver the aerosolized agent in a volume lower than the tidal volume of the guinea pigs. The average particle size of the nerve agent delivered was 1.48 +/- 0.07 micrometer. The microinstillation technology has been validated by exposing the animals to Coomassie brilliant blue, which showed a uniform distribution of the dye in different lung lobes. In addition, the concentration of the dye in the lungs correlated with the dose/time of exposure. Furthermore, histopathological analysis confirmed the absence of barotraumas following micoinstillation. This novel technique delivers the agent safely, requires less amount of agent, avoids exposure to skin, pelt, and eye, and circumvents the concern of deposition of the particles in the nasal and palette due to the switching of breathing from nasal to oronasal in whole-body dynamic chamber or nose only exposure. Currently, we are using this inhalation exposure technique to investigate lung injuries and respiratory disturbances following direct exposure to VX.

Production of malodorous steroids from androsta-5,16-dienes and androsta-4,16-dienes by Corynebacteria and other human axillary bacteria.

The biotransformations of a number of steroids, chiefly 5,6,16,17-tetradehydro-androstanes, are reported. The strains investigated were Corynebacteria sp. G38, G40, G41, B, Brevis sp. CW5 and Micrococcus sp. M-DH2. Corynebacterium sp. G41 proved remarkably efficient in effecting oxidative isomerisation of 5-ene-3-sterols into the corresponding 4-en-3-ones. The main biochemical reactions involved were oxidation at C-3; no reduction processes were observed. Conversions of 3beta-sterols into the C-3 oxo-steroids were high, but were correspondingly low for the 3alpha-sterol epimers. Androsta-4,16-dien-3-one and 5beta-androsta-16-en-3-one are crucial to the formation of malodour. The rate of formation of these compounds was measured over 72 h incubation periods using three substrates: androsta-5,16-dien-3beta-ol, androsta-4,16-dien-3beta-ol and androsta-5,16-dien-3-one. Induction studies of the transformation of the androsta-5,16-dien-3beta-ol into the very odorous compound androsta-4,16-dien-3-one showed that cells incubated with a mixture of antibiotics displayed the same extent of biotransformation as normal cells if the concentration of antibiotic was low (1, 3, 5 and 7 microg/ml), although at concentrations higher than 10 microg/ml, biotransformation yields were reduced. Pre-incubation with a 3beta-fluoro-steroid inhibited the formation of the odorous androsta-4,16-dien-3-one.