Early detection of delirium in older medical inpatients: prodrome, predictors and motor subtyping

Background Delirium is highly prevalent, especially in older patients. It independently leads to adverse outcomes, but remains under-detected, particularly hypoactive forms. Although early identification and intervention is important, delirium prevention is key to improving outcomes. The delirium prodrome concept has been mooted for decades, but remains poorly characterised. Greater understanding of this prodrome would promote prompt identification of delirium-prone patients, and facilitate improved strategies for delirium prevention and management. Methods Medical inpatients of ≥70 years were screened for prevalent delirium using the Revised Delirium Rating Scale (DRS--‐R98). Those without prevalent delirium were assessed daily for delirium development, prodromal features and motor subtype. Survival analysis models identified which prodromal features predicted the emergence of incident delirium in the cohort in the first week of admission. The Delirium Motor Subtype Scale-4 was used to ascertain motor subtype. Results Of 555 patients approached, 191 patients were included in the prospective study. The median age was 80 (IQR 10) and 101 (52.9%) were male. Sixty-one patients developed incident delirium within a week of admission. Several prodromal features predicted delirium emergence in the cohort. Firstly, using a novel Prodromal Checklist based on the existing literature, and controlling for confounders, seven predictive behavioural features were identified in the prodromal period (for example, increasing confusion; and being easily distractible). Additionally, using serial cognitive tests and the DRS-R98 daily, multiple cognitive and other core delirium features were detected in the prodrome (for example inattention; and sleep-wake cycle disturbance). Examining longitudinal motor subtypes in delirium cases, subtypes were found to be predominantly stable over time, the most prevalent being hypoactive subtype (62.3%). Discussion This thesis explored multiple aspects of delirium in older medical inpatients, with particular focus on the characterisation of the delirium prodrome. These findings should help to inform future delirium educational programmes, and detection and prevention strategies.

Bioengineering strategies to improve functional qualities of nisin

The abuse of antibiotics and the emergence of multi-drug resistant bacterial strains have created the need to explore alternative methods of controlling microbial pathogens. The bacteriocin family of antimicrobial peptides has been proposed as one such alternative to classic antibiotics. Nisin A belongs to the subgroup of bacteriocins called the lantibiotics, which contain several unusual amino acids as a consequence of enzyme-mediated post-translational modifications. As nisin is produced by generally regarded as safe (GRAS) microorganisms, it could potentially be applied in a clinical setting. However, as lantibiotics are naturally produced in such small quantities, this can hinder their industrial potential. In order to overcome this, several approaches can be utilised. For example, given the gene encoded nature of lantibiotics, genetic engineering approaches can be implemented in order to yield variants with enhanced properties. Here, the use of mutagenesis-based strategies was employed to obtain a derivative of nisin with enhanced bioactivity in vitro. Investigations with purified peptide highlighted the enhanced specific activity of this variant, nisin M21V, against food-borne Listeria monocytogenes strains. Furthermore, this specific enhanced bioactivity was evident in a mouse model of listeriosis. Reductions in bioluminescence and microbial counts in organs from infected mice were observed following treatment with nisin M21V compared to that of wild-type nisin A. Peptide bioengineering approaches were also implemented to obtain additional novel derivatives of nisin. The generation of “S5X” and “S33X” banks (representing a change of natural serines at positions 5 and 33 to all possible alternative residues) by a combination of site-saturation and site-directed mutagenesis led to the identification of several derivatives exhibiting improved stability. This allowed the rational design of variants with enhanced stability compared to that of wild type nisin. Another means of tackling issues associated with lantibiotic yield is to combine lantibiotics with other antimicrobials. This could circumvent the need for enhanced production while also reducing concentrations of the peptide antimicrobials. We observed that combinations of nisin variants and low levels of plant essential oils (thymol, carvacrol, trans-cinnamaldehyde) significantly controlled Gram negative foodborne pathogens in in vitro assays compared to nisin A-essential oil combinations. This enhanced control was also evident in model food systems. Nisin variants used in conjunction with carvacrol significantly reduced numbers of E. coli O157:H7 in apple juice while a commercial nisin preparation used in combination with citric acid significantly controlled C. sakazakii in infant milk formula. It is noteworthy that while nisin is generally associated with Gram positive targets, upon combination with plant essential oils the spectrum of inhibition was broadened to Gram negative targets.

Pairs trading in the UK equity market: risk and return

In this paper, we provide the first comprehensive UK evidence on the profitability of the pairs trading strategy. Evidence suggests that the strategy performs well in crisis periods, so we control for both risk and liquidity to assess performance. To evaluate the effect of market frictions on the strategy, we use several estimates of transaction costs. We also present evidence on the performance of the strategy in different economic and market states. Our results show that pairs trading portfolios typically have little exposure to known equity risk factors such as market, size, value, momentum and reversal. However, a model controlling for risk and liquidity explains a far larger proportion of returns. Incorporating different assumptions about bid-ask spreads leads to reductions in performance estimates. When we allow for time-varying risk exposures, conditioned on the contemporaneous equity market return, risk-adjusted returns are generally not significantly different from zero.