BackgroundOlder patients are at an increased risk of developing adverse drug reactions (ADR). Of particular concern are the oldest old, which constitute an increasingly growing population. Having a validated clinical tool to identify those older patients at risk of developing an ADR during hospital stay would enable healthcare staff to put measures in place to reduce the risk of such an event developing. The current study aimed to (1) develop and (2) validate an ADR risk prediction model.MethodsWe used a combination of univariate analysis and multivariate binary logistic regression to identify clinical risk factors for developing an ADR in a population of older people from a UK teaching hospital. The final ADR risk model was then validated in a European population (European dataset).ResultsSix-hundred-ninety patients (median age 85 years) were enrolled in the development stage of the study. Ninety-five reports of ADR were confirmed by independent review in these patients. Five clinical variables were identified through multivariate analysis and included in our final model; each variable was attributed a score of 1. Internal validation produced an AUROC of 0.74, a sensitivity of 80%, and specificity of 55%. During the external validation stage the AUROC was 0.73, with sensitivity and specificity values of 84% and 43% respectively.ConclusionsWe have developed and successfully validated a simple model to use ADR risk score in a population of patients with a median age of 85, i.e. the oldest old. The model is based on 5 clinical variables (≥8 drugs, hyperlipidaemia, raised white cell count, use of anti-diabetic agents, length of stay ≥12 days), some of which have not been previously reported.

In recent years, novel model systems have made significant contributions to our understanding of the processes that control the ageing of whole organisms. However, there are limited data to show that the mechanisms that gerontologists have identified as having a role in organismal ageing contribute significantly to the ageing of the central nervous system. Two recent discoveries illustrate this particularly well. The first is the consistent failure of researchers to demonstrate a simple relationship between organismal ageing and oxidative stress--a mechanism often assumed to have a primary role in brain ageing. The second is the demonstration that senescent cells play a causal part in organismal ageing but remain essentially unstudied in a CNS context. We argue that the animal models now available (including rodents, flies, molluscs and worms), if properly applied, will allow a paradigm shift in our current understanding of the normal processes of brain ageing.

Admission to a specialist HAU was associated with a significant reduction in PIMS. Very few patients discharged with a PIM had a documented follow-up plan. PIM prevalence was lower than published rates found internationally. Similar studies in settings of varying types across the UK are needed.

ObjectiveThe roll-out of the Pfizer-BioNTech BNT162b2 COVID-19 vaccine has brought many logistical challenges, such as the absence of comprehensive stability data leading to strict handling instructions during dilution and administration. Accidental mishandling therefore presents challenging clinical dilemmas, which often led vaccine providers to err on the side of caution and discard mishandled vials rather than risk administering ineffective vaccine. This study aims to answer key questions about the vaccine’s stability to allow for a more informed decision-making process should a non-conformity occur.MethodsResidual vaccine in freshly used, but appropriately stored vials collected from vaccination centres in Brighton, UK, were tested after exposure to various handling conditions and analysed by dynamic light scattering to determine the size of the lipid-mRNA nanoparticles, and gel electrophoresis to visualise the mRNA integrity and separation from the lipid formulation.ResultsKnocking or dropping vaccine samples from small heights resulted in lowest levels of instability, indicating low risk of compromising clinical efficacy. However, repeated drawing and injecting through 23 G needles at high speed and, more significantly, shaking and vortexing led to progressive increase in the size and polydispersity index of the lipid-mRNA nanoparticles, coupled with or caused by up to ~50% release of mRNA from the lipid formulation. This is thought to impact the vaccine’s efficacy due to lack of free mRNA protection and cellular internalisation.ConclusionsThese results reiterate the importance of adhering to the manufacturer’s instructions on handling, especially with regard to shaking and exposing the vaccine to excessive vibration.

During aging, the Ca 2+ sensitive slow afterhyperpolarization (sAHP) of hippocampal neurons is known to increase in duration. This change has also been observed in the serotonergic cerebral giant cells (CGCs) of the pond snail Lymnaea stagnalis, but has yet to be characterized. In this paper, we confirm that there is a reduction in firing rate, an increase in the duration of the sAHP, and an alteration in the strength and speed of spike frequency adaptation (SFA) in the CGCs during aging, a finding that is compatible with an increase in a sAHP current. We go on to show that age-related changes in the kinetics of SFA are consistent with a reduction in Ca 2+ clearance from the cell, which we confirm with Ca 2+ imaging and pharmacological manipulation of the sodium calcium exchanger (NCX). These experiments suggest that the NCX may be switching to a reverse-mode configuration in the CGCs during aging.3

Background: Warfarin is commonly initiated post-cardiac surgery to reduce the risk of intracardiac thrombus formation. Studies have found that sensitivity is increased after cardiac surgery and anticoagulation is subsequently difficult to manage. This study set out to identify clinical markers of increased warfarin sensitivity in patients after cardiac surgery, and build a model that can predict warfarin sensitivity, and improve safety in this setting. Methods: The study was an observational, retrospective cohort design. Clinical parameters including left ventricular ejection fraction (LVEF), cross-clamp time, age, serum albumin and C-reactive protein concentrations were collected from consenting patients who had undergone cardiac surgery and were prescribed postoperative warfarin. The warfarin dose index (WDI) was calculated for each patient from their international normalized ratio (INR) and warfarin dose, as a measure of sensitivity. Results: A total of 41 patients were recruited to the study. Logarithmically transformed WDI (log WDI) significantly correlated with LVEF, cardiopulmonary bypass (CPB) time, crossclamp time, baseline INR and co-administration of amiodarone (p < 0.05). When added to a linear regression model, LVEF and cross-clamp time produced a model that accounted for 41% of the variance in log WDI (R 2 = 0.41), p = 0.0002). Applying a log WDI cutoff value of −0.349 discriminated between patients who develop an INR > 4 and those who do not, with a sensitivity of 75% and a specificity of 70%. Conclusions: This single-centre study has highlighted two risk factors for increased warfarin sensitivity post-cardiac surgery. Further research is needed to confirm these findings in a wider, more diverse population, and to validate this model.

Susceptibility to adverse drug reactions (ADRs), multimorbidity, and frailty are associated with human aging, yet there is wide variation in the severity and age at which individuals are afflicted. Identifying genetic markers of increased risk of this phenotype would help stratify individuals to specialist interventions. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates a cell’s response to stressors, including the expression of enzymes involved in drug metabolism. Its expression has been shown to decline in animal aging models. In this study, we tested the hypothesis that Nrf2 gene (NFE2L2) transcription/translation decline in human aging and that single-nucleotide polymorphisms (SNPs) in the NFE2L2 gene are associated with increased ADR risk, multimorbidity, and frailty in older people. Gene expression and protein levels were measured in peripheral blood mononuclear cells donated from healthy patients aged 18–80 years old. NFE2L2 genotypes were determined at three loci in a subpopulation of patients recruited to the PRIME study (a multicenter prospective cohort study that followed older adults for 8 weeks post-discharge to determine ADR). Both NFE2L2 gene and Nrf2 protein expression declined significantly with age in human peripheral blood mononuclear cells. In the PRIME substudy population, the rs35652124 NFE2L2 SNP was associated with increased ADR risk and decreased frailty and multimorbidity scores.

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