Theoretically quantifying the direct and indirect benefits of vaccination against SARS-CoV-2 in terms of avoided deaths.

The Coronavirus Disease 2019 (COVID)-19 pandemic has placed unprecedented pressures on societies around the world. Successful vaccines, developed against the spike protein of the Severe Acute Respiratory Syndrome Virus 2 (SARS-CoV-2) virus, offer hope that new hospitalisations and new deaths will subside. However, vaccination takes place in a dynamic environment. For example, new variants of the disease may occur where the effectiveness of a vaccine lies below that of the original target of the vaccine, while changes in the behaviour of a population are accompanied by a changed basic reproduction number. Here, we aim to understand how changes in values of basic parameters affect the benefits of vaccination at the direct level, of the individuals vaccinated, and at the indirect level, of the wider, unvaccinated community. We work within the framework of a Susceptible-Infected-Recovered model, and produce a metric for the benefits of vaccination, at both direct and indirect levels, in terms of the number of avoided deaths. Taking into account the initial prevalence of a SARS-CoV-2 infection, the mortality rate of the disease, the basic reproduction number, the vaccination rate, and the effectiveness of a vaccine, we explore how these basic parameters affect the benefits of vaccination. We find a range of situations where indirect benefits of vaccination outweigh direct benefits. This especially occurs at lower rates of vaccination (20% - [Formula: see text]) and intermediate values of the basic reproduction number (1-1.5). The indirect benefits can be substantial, in some cases being more than 400% of the direct benefits. For an initial prevalence of SARS-CoV-2 infection of 2%, a basic reproduction number of 1.2, a mortality rate of 2%, and a vaccine effectiveness of 95%, our findings show, for a population of 500,000 people, where 100,000 susceptible individuals are vaccinated, that approximately 2200 deaths are avoided. However, approximately 600 of these deaths are avoided amongst vaccinated individuals, while approximately 1600 deaths are avoided in the wider, unvaccinated community.

Clinical decision-making and dispensing performance in pharmacy students and its relationship to executive function and implicit memory.

Background: When providing pharmaceutical care, the pharmacist relies upon a clinical decision-making process that involves information gathering, clinical reasoning, and clinical judgment. Typically, pharmacists have to identify, retain and recall numerous pieces of key information arranged spatially in medical records and prescriptions or verbally from colleagues when making decisions. Executive function, including spatial working memory and verbal reasoning, along with other cognitive domains, will likely contribute to the elements that comprise this process. Objective: To establish the predictive utility of markers of executive function and implicit memory on clinical decision-making and dispensing performance in pharmacy students. Methods: MPharm students from two sites completed a battery of cognitive tasks designed to measure elements of executive and other cognitive functions (e.g., verbal working memory (VWM), visuospatial working memory (VSWM), and implicit memory (IM)). Performance on 2 clinical case studies was used to assess clinical decision-making ability (n = 16), and a prescription screening and dispensing assessment was used to assess dispensing accuracy (n = 32). A statistical model was built to establish whether executive and other cognitive functions markers can predict clinical decision-making and dispensing performance. Results: Performance in VSWM test and IM tests were found to explain approximately 63% of the deviance in clinical decision-making ability (null residual deviance = 49.4, deviance explained by variables = 31.0; Matrix Model p < 0.01, Dot-clearing test p < 0.01). Performance is the VSWM, and VWM tests explained approximately 30% of the deviance in the dispensing task (null residual deviance = 7596.7, deviance explained by variables = 2099.3; Matrix Model*Baddeley Reasoning Model, p < 0.05). Conclusion: The results suggest that specific cognitive domains contribute to the clinical decision-making process. This adds to a growing body of literature that highlights the importance of person-specific factors in predicting clinical competence.

Improved estimates of mean pharmacokinetic parameters for increased accuracy in dosing and reduced risk to patients.

AIMS: Pharmacokinetic equations, which relate different parameters of a single individual, are often applied to reported mean parameter-values, with the aim of estimating the mean value of an unreported parameter. Due to population heterogeneity this approach generally leads to errors in their estimation. We provide details of this source of error. Our aim is to take into account the effects of population heterogeneity in commonly used pharmacokinetic models. This provides improved estimates and knowledge of the concentration of a drug in the plasma over time. METHODS: Inequalities and approximations for corrected mean estimates are derived. These results are then applied to published clinical-trial data to illustrate their accuracy in practical situations. RESULTS: By using mean values within the pharmacokinetic equations for a single individual, we show that estimates of mean parameter values, for a variety of dosing regimens, generally have errors. Using published clinical trial data, we show that such estimates can systematically deviate from the exact mean value by up to 19%. We provide analytical results, which amount to inequalities when there are systematic deviations from exact results, along with approximate results that improve the accuracy of estimates. CONCLUSIONS: Medical, pharmacy and nursing students should be educated about errors and inequalities that can arise when transforming reported mean values of pharmacokinetic parameters into the mean values of parameters that are required, but not reported. Using approximate results, that correct estimates of mean parameter values so that they more accurately reflect actual average values, may provide a practical solution.

Stability testing of the Pfizer-BioNTech BNT162b2 COVID-19 vaccine: a translational study in UK vaccination centres.

OBJECTIVE: The 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. METHODS: Residual 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. RESULTS: Knocking 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. CONCLUSIONS: These 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.

The Association of a Single-Nucleotide Polymorphism in the Nuclear Factor (Erythroid-Derived 2)-Like 2 Gene With Adverse Drug Reactions, Multimorbidity, and Frailty in Older People.

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.

Estimating a drug's elimination rate-constant or half-life from a single blood sample: a practical approach with particular benefits for critically ill/vulnerable patients.

In this paper we present a mathematical solution that allows the elimination rate-constant or half life of a drug to be estimated from a single blood drug measurement. This is of great utility in clinical areas involving care of criticallly ill or vulnerable patients, where providing more than one blood sample can involve significant risks. The calculations used in our approach, based solely on a single sample, do not require complex pharmacokinetic software, but instead can be simply performed at the patient's bedside using standard personal computing tools. The proposed method allows a personalised estimate of the drug's half life, which is preferable to using population averages, or using estimates based on proxy markers of lagging organ function, which are both indirect and generally inaccurate for a patient with confounding factors.

Identification of clinical factors predicting warfarin sensitivity after cardiac surgery.

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, cross-clamp 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 (R2 = 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.

Does the 5-HT1A rs6295 polymorphism influence the safety and efficacy of citalopram therapy in the oldest old?

Major depressive disorder (MDD) in older people is a relatively common, yet hard to treat problem. In this study, we aimed to establish if a single nucleotide polymorphism in the 5-HT1A receptor gene (rs6295) determines antidepressant response in patients aged > 80 years (the oldest old) with MDD. Nineteen patients aged at least 80 years with a new diagnosis of MDD were monitored for response to citalopram 20 mg daily over 4 weeks and genotyped for the rs6295 allele. Both a frequentist and Bayesian analysis was performed on the data. Bayesian analysis answered the clinically relevant question: 'What is the probability that an older patient would enter remission after commencing selective serotonin reuptake inhibitor (SSRI) treatment, conditional on their rs6295 genotype?' Individuals with a CC (cytosine-cytosine) genotype showed a significant improvement in their Geriatric Depression Score (p = 0.020) and cognition (p = 0.035) compared with other genotypes. From a Bayesian perspective, we updated reports of antidepressant efficacy in older people with our data and calculated that the 4-week relative risk of entering remission, given a CC genotype, is 1.9 [95% highest-density interval (HDI) 0.7-3.5], compared with 0.52 (95% HDI 0.1-1.0) for the CG (cytosine-guanine) genotype. The sample size of n = 19 is too small to draw any firm conclusions, however, the data suggest a trend indicative of a relationship between the rs6295 genotype and response to citalopram in older patients, which requires further investigation.

A switch in the mode of the sodium/calcium exchanger underlies an age-related increase in the slow afterhyperpolarization.

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 article, 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 in the CGCs during aging, a finding that is compatible with an increase in the sAHP current. We go on to show that age-related changes in the kinetics of spike frequency adaptation 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. These experiments suggest that the sodium calcium exchanger may be switching to a reverse-mode configuration in the CGCs during aging.

Development and validation of a risk model for predicting adverse drug reactions in older people during hospital stay: Brighton Adverse Drug Reactions Risk (BADRI) model.

BACKGROUND: Older 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. METHODS: We 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). RESULTS: Six-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. CONCLUSIONS: We 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.

Potentially inappropriate prescribing in patients on admission and discharge from an older peoples' unit of an acute UK hospital.

BACKGROUND: The Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) classifies 65 common drug issues found to contribute to inappropriate prescribing in the elderly. International studies using STOPP criteria indicate high potentially inappropriate medication (PIM) prevalence rates; however, no studies have been conducted in older patients in UK hospitals. Published literature has not assessed whether prescribers attempt to minimise the potential risk of PIMs by putting in place follow-up or review plans. OBJECTIVES: The objectives of this study were (1) to determine prevalence and types of PIMs in older people admitted to and discharged from a UK hospital; and (2) to determine how often PIMs prescribed on discharge are accompanied by a plan for follow-up. METHODS: This was a retrospective, non-randomised study conducted in the Specialist Health and Ageing Unit (HAU) of a 950-bed acute hospital trust in England, UK. The subjects were patients aged ≥65 years admitted to the HAU in June and July 2011. Data were obtained by applying STOPP criteria to electronic admission and discharge medication lists. Parametric and non-parametric tests were performed to assess variables and to detect differences between groups. A PIM index was calculated by dividing the total number of PIMs by the total number of medications. RESULTS: Medication lists for 195 patients were assessed. Median age was 85.5 years. The median number of admission medicines was nine. A total of 66 patients (34 %) were prescribed more than ten medications. The median number of discharge medicines was ten, with 80 patients (41 %) prescribed more than ten medicines. Admission PIM prevalence was 26.7 % (95 % CI 20.5-32.9; 52 patients, 74 PIMs). The most common PIM categories on admission were central nervous system (CNS) and psychotropic drugs, drugs adversely affecting patients at risk of falls and drugs acting on the urogenital system. The likelihood of having a PIM on admission was doubled in patients receiving more than ten medications compared with those taking fewer (odds ratio 2.3 [95 % CI 1.2-4.4]; p = 0.01). Discharge PIM prevalence was 22.6 % (95 % CI 16.7-28.5; 44 patients, 51 PIMs). PIMs reduced significantly on discharge (p = 0.005). The most common discharge PIMs were drugs adversely affecting patients at risk of falls, CNS and psychotropics, urogenital drugs and cardiovascular agents. Advice for general practitioners to monitor medication was documented on the discharge summary of three patients. An index was developed, based on the ratio of PIMs to medication totals. The PIM index complements the assessment of PIM prevalence and allows comparison of prescribing appropriateness between populations and between studies by taking into account the total amount of prescribed medication. Despite an increase in medication prescribed, the PIM index (rate) decreased from 0.043 on admission to 0.027 at discharge. CONCLUSIONS: 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.

Insights into CNS ageing from animal models of senescence.

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.