Viral vector use in gene therapy has highlighted several safety concerns, including genotoxic events. Generally, vector-mediated genotoxicity results from upregulation of cellular proto-oncogenes via ...promoter insertion, promoter activation, or gene transcript truncation, with enhancer-mediated activation of nearby genes the primary mechanism reported in gene therapy trials. Vector-mediated genotoxicity can be influenced by virus type, integration target site, and target cell type; different vectors have distinct integration profiles which are cell-specific. Non-viral factors, including patient age, disease, and dose can also influence genotoxic potential, thus the choice of test models and clinical trial populations is important to ensure they are indicative of efficacy and safety. Efforts have been made to develop viral vectors with less risk of insertional mutagenesis, including self-inactivating (SIN) vectors, enhancer-blocking insulators, and microRNA targeting of vectors, although insertional mutagenesis is not completely abrogated. Here we provide an overview of the current understanding of viral vector-mediated genotoxicity risk from factors contributing to viral vector-mediated genotoxicity to efforts made to reduce genotoxicity, and testing strategies required to adequately assess the risk of insertional mutagenesis. It is clear that there is not a 'one size fits all' approach to vector modification for reducing genotoxicity, and addressing these challenges will be a key step in the development of therapies such as CRISPR-Cas9 and delivery of future gene-editing technologies.
To date, research on adverse drug reactions (ADRs) has focused on secondary care, and there is a paucity of studies that have prospectively examined ADRs affecting older adults in general practice.
...To examine the cumulative incidence and severity of ADRs and associated patient characteristics in a sample of community-dwelling older adults.
Prospective cohort study of older adults (aged ≥70 years,
= 592) recruited from 15 general practices in the Republic of Ireland.
Manual review of the participant's general practice electronic medical record, linked to the national dispensed prescription medicine database, and a detailed, self-reported patient postal questionnaire. The primary outcomes were ADR occurrence and severity over a 6-year period (2010-2016). Unadjusted and adjusted logistic regression models examined potential associations between patient characteristics and ADR occurrence.
A total of 211 ADRs were recorded for 159 participants, resulting in a cumulative incidence of 26.9% over 6 years. The majority of ADRs detected were mild (89.1%), with the remainder classified as moderate (10.9%). Eight moderate ADRs, representing 34.8% of moderate ADRs and 3.8% of all ADRs, required an emergency hospital admission. ADRs were independently associated with female sex (adjusted odds ratio OR 1.83, 95% confidence interval CI = 1.17 to 2.85;
= 0.008), polypharmacy (5-9 drug classes) (adjusted OR 1.81, 95% CI = 1.17 to 2.82;
= 0.008), and major polypharmacy (≥10 drug classes) (adjusted OR = 3.33, 95% CI = 1.62 to 6.85;
= 0.001).
This prospective cohort study of ADRs in general practice shows that over one-quarter of older adults experienced an ADR over a 6-year period. Polypharmacy is independently associated with ADR risk in general practice and older adults on ≥10 drug classes should be prioritised for regular medication review.
•Changes in depression symptomology among community dwelling older adults living in Ireland were examined over a 4-year period using group- based trajectory modelling techniques.•Four distinct ...trajectories were identified as (1) a stable low symptom level group (79%), (2) a moderate but deteriorating symptoms group (7.6%), (3) a moderate but improving group (10.1%) and (4) a vulnerable group with consistently high symptoms (3.1%).•Such classes were associated with reported experiences of limiting pain, mobility impairments, stress and loneliness.
This study investigated the role of a large range psychological, attitudinal and health related variables as predictors of depression trajectories amongst older adults over a 4-year time period.
Data from three consecutive waves of the TILDA survey of older community dwelling adults aged 50+ in Ireland were combined for analysis. Depression symptom scores were assessed using the Center for Epidemiological Studies– Depression scale (CES-D). Changes in depression scores over three time points were modelled as distinct trajectory classes using group-based trajectory modelling, whilst simultaneously controlling for demographic, attitudinal and health related predictors of these trajectory classes using multinomial regression.
Four distinct depression trajectories were identified as (1) a stable low symptom level group (79%), (2) a moderate but deteriorating symptoms group (7.6%), (3) a moderate but improving group (10.1%) and (4) a vulnerable group with consistently high symptoms (3.1%). Multinomial logistic regression indicated that limiting pain, mobility impairments, perceived stress and loneliness predicted membership of the moderate and higher depressive symptom classes. Retirement status and higher reported levels of worry were associated with a greater likelihood of membership of the moderate symptom classes only.
Use of the CES-D is open to bias due to subjective nature of respondent reporting.
Results concur with previous studies on the development of depression among older people and highlight the key health related and psychological variables that may inform interventions aimed at mitigating risks of developing depression among older adults.
To provide a comprehensive analysis of small molecule genotoxic potential we have developed and validated an automated, high-content, high throughput, image-based in vitro Micronucleus (IVM) assay. ...This assay simultaneously assesses micronuclei and multiple additional cellular markers associated with genotoxicity. Acoustic dosing (≤ 2 mg) of compound is followed by a 24-h treatment and a 24-h recovery period. Confocal images are captured Cell Voyager CV7000 (Yokogawa, Japan) and analysed using Columbus software (PerkinElmer). As standard the assay detects micronuclei (MN), cytotoxicity and cell-cycle profiles from Hoechst phenotypes. Mode of action information is primarily determined by kinetochore labelling in MN (aneugencity) and γH2AX foci analysis (a marker of DNA damage). Applying computational approaches and implementing machine learning models alongside Bayesian classifiers allows the identification of, with 95% accuracy, the aneugenic, clastogenic and negative compounds within the data set (Matthews correlation coefficient: 0.9), reducing analysis time by 80% whilst concurrently minimising human bias. Combining high throughput screening, multiparametric image analysis and machine learning approaches has provided the opportunity to revolutionise early Genetic Toxicology assessment within AstraZeneca. By multiplexing assay endpoints and minimising data generation and analysis time this assay enables complex genotoxicity safety assessments to be made sooner aiding the development of safer drug candidates.
Abstract
Background
People living with multimorbidity may hold complex beliefs about medicines, potentially influencing adherence. Polynomial regression offers a novel approach to examining the ...multidimensional relationship between medication beliefs and adherence, overcoming limitations associated with difference scores.
Purpose
To explore the multidimensional relationship between medication beliefs and adherence among people living with multimorbidity.
Methods
Secondary analysis was conducted using observational data from a cohort of older adults living with ≥2 chronic conditions, recruited from 15 family practices in Ireland in 2010 (n = 812) and followed up in 2012 (n = 515). Medication beliefs were measured with the Beliefs about Medicines Questionnaire-Specific. Adherence was assessed with the medication possession ratio using prescription data from the national primary care reimbursement service. Polynomial regression was used to explore the best-fitting multidimensional models for the relationship between (i) beliefs and adherence at baseline, and (ii) beliefs at baseline and adherence at follow-up.
Results
Confirmatory polynomial regression rejected the difference-score model, and exploratory polynomial regression indicated quadratic models for both analyses. Reciprocal effects were present in both analyses (slope Analysis 1: β = 0.08, p = .007; slope Analysis 2: β = 0.07, p = .044), indicating that adherence was higher when necessity beliefs were high and concern beliefs were low. Nonreciprocal effects were also present in both analyses (slope Analysis 1: β = 0.05, p = .006; slope Analysis 2: β = 0.04, p = .043), indicating that adherence was higher when both necessity and concern beliefs were high.
Conclusions
Among people living with multimorbidity, there is evidence that the relationship between medication beliefs and adherence is multidimensional. Attempts to support adherence should consider the combined role of necessity and concern beliefs.
A difference-score model was not appropriate for exploring the association between the Necessity-Concerns Framework and adherence among people living with multimorbidity, with evidence suggesting the relationship between medication beliefs and adherence is multidimensional in this cohort.
Lay Summary
When people live with multiple ongoing health conditions, they might have complex beliefs about their prescribed medicines. These beliefs could relate to the perceived necessity of medicines (necessity beliefs) and perceived concerns about medicines (concern beliefs). This study aimed to explore how necessity and concern beliefs, in combination, relate to the extent to which people living with multiple ongoing conditions take their medicines as prescribed. The study analyzed an existing dataset that included 812 older adults recruited via family practice settings in Ireland in 2010. Of these, 515 people were followed up again in 2012. All participants were living with at least two ongoing health conditions. Participants self-reported their medication-related necessity and concern beliefs by completing a questionnaire. Their level of medication taking was calculated using pharmacy records. The results showed that having a combination of high necessity beliefs and low concern beliefs was related to higher levels of medication taking than having a combination of low necessity beliefs and high concern beliefs. Having a combination of high necessity beliefs and high concern beliefs was related to higher levels of medication taking than having a combination of low necessity beliefs and low concern beliefs. Attempts to support patients to take their medicines should consider the combined role of their necessity and concern beliefs on behavior.
Background
Older adults likely exhibit considerable differences in healthcare need and usage. Identifying differences in healthcare utilisation both between and within individuals over time may ...support future service development.
Objectives
To characterise temporal changes in healthcare utilisation among a nationally representative sample of community-dwelling older adults.
Methods
A latent transition analysis of the first three waves of The Irish Longitudinal Study on Ageing (TILDA) (N = 6128) was conducted.
Results
Three latent classes of healthcare utilisation were identified, ‘primary care only’; ‘primary care and outpatient visits’ and ‘multiple utilisation’. The classes were invariant across all three waves. Transition probabilities indicated dynamic changes over time, particularly for the ‘primary care and outpatient visits’ and ‘multiple utilisation’ statuses.
Discussion
Older adults exhibit temporal changes in healthcare utilisation which may reflect changes in healthcare need and disease progression. Further research is required to identify the factors which influence movement between healthcare utilisation patterns.
Measuring Burnout in Social Work Doherty, Ann S.; Mallett, John; Leiter, Michael P. ...
European journal of psychological assessment : official organ of the European Association of Psychological Assessment,
2021, Volume:
37, Issue:
1
Journal Article
Peer reviewed
Several studies challenge the three-dimensional structure
of the Maslach Burnout Inventory - Human Services Survey (MBI-HSS),
citing alternative measurement models including bifactor models. While ...bifactor
models have merit, if data sampling violates assumptions of Stochastic
Measurement Theory (SMT) the bifactor model requires modification prior to
application. The present study compared five alternative MBI-HSS factor models
using both Confirmatory Factor Analysis (CFA) and Exploratory Structural
Equation Modeling (ESEM). Data from a cross-sectional survey of United Kingdom
(UK) social workers were examined (N = 1257),
with validation analyses conducted in an independent sample
(N = 162). Bifactor models, re-specified to
account for SMT, provided good fit. However, improved fit was observed for a
bifactor-ESEM specification, in both test
(χ2 = 1,112.93,
df = 149,
p < .001, CFI = .969,
RMSEA = .072, 90% CI .068, .076) and validation
(χ2 = 227.89,
df = 149,
p < .001, CFI = .978,
RMSEA = .057, 90% CI .042, .072) samples. The results confirm
the MBI-HSS possesses a bifactor structure in UK social workers when SMT is
considered, and that bifactor-ESEM may provide a better framework to examine
MBI-HSS.
Abstract Introduction Problematic polypharmacy is the prescribing of five or more medications potentially inappropriately. Unintentional prescribing cascades represent an under-researched aspect of ...problematic polypharmacy and occur when an adverse drug reaction (ADR) is misinterpreted as a new symptom resulting in the initiation of a new medication. The aim of this study was to elicit key stakeholders’ perceptions of and attitudes towards problematic polypharmacy, with a focus on prescribing cascades. Methods qualitative one-to-one semi-structured interviews were conducted with predefined key stakeholder groups. Inductive thematic analysis was employed. Results Thirty-one stakeholders were interviewed: six patients, two carers, seven general practitioners, eight pharmacists, four hospital doctors, two professional organisation representatives and two policymakers. Three main themes were identified: (i) ADRs and prescribing cascades—a necessary evil. Healthcare professionals (HCPs) expressed concern that experiencing an ADR would negatively impact patients’ confidence in their doctor. However, patients viewed ADRs pragmatically as an unpredictable risk. (ii) Balancing the risk/benefit tipping point. The complexity of prescribing decisions in the context of polypharmacy made balancing this tipping point challenging. Consequently, HCPs avoided medication changes. (iii) The minefield of medication reconciliation. Stakeholders, including patients and carers, viewed medication reconciliation as a perilous activity due to systemic communication deficits. Conclusion Stakeholders believed that at a certain depth of polypharmacy, the risk that a new symptom is being caused by an existing medication becomes incalculable. Therefore, in the absence of harm, medication changes were avoided. However, medication reconciliation post hospital discharge compelled prescribing decisions and was seen as a high-risk activity by stakeholders.
Micronucleus (MN) assessment is a valuable tool in safety assessment. However, several compounds are positive in the in vivo bone marrow (BM) MN assay but negative in vitro, reflecting that BM ...complexity is not recapitulated in vitro. Importantly, these compounds are not genotoxic; rather, drug-driven pharmacological-effects on the BM increase MN, however, without mechanistic understanding, in vivo positives stop drug-progression. Thus, physiologically-relevant BM models are required to bridge the gap between in vitro and in vivo. The current study aimed to investigate the utility of two human 3D BM models (fluidic and static) for MN assessment. MN induction following treatment with etoposide and Poly-ADP Ribose Polymerase inhibitor (PARPi) and prednisolone (negative in vitro, positive in vivo) was determined in 2D L5178Y and human BM cells, and the 3D BM models. Etoposide (0-0.070 µM) and PARPi (0-150 µM) induced MN in both 3D BM models indicating their utility for genotoxicity testing. Interestingly, PARPi treatment induced a MN trend in 3D more comparable to in vivo. Importantly, prednisolone (0-1.7 mM) induced MN in both 3D BM models, suggesting recapitulation of the in vivo microenvironment. These models could provide a valuable tool to follow up, and eventually predict, suspected pharmacological mechanisms, thereby reducing animal studies.
•The IWGT evaluated high information content data streams for genotoxicity testing.•Strengths, weaknesses, opportunities, and threats were considered.•Strengths include high throughput and provision ...of mechanistic insight.•Immediate uses include screening, prioritization and integrated testing.
We live in an era of ‘big data’, where the volume, velocity, and variety of the data being generated is increasingly influencing the way toxicological sciences are practiced. With this in mind, a workgroup was formed for the 2017 International Workshops on Genotoxicity Testing (IWGT) to consider the use of high information content data in genetic toxicology assessments. Presentations were given on adductomics, global transcriptional profiling, error-reduced single-molecule sequencing, and cellular phenotype-based assays, which were identified as methodologies that are relevant to present-day genetic toxicology assessments. Presenters and workgroup members discussed the state of the science for these methodologies, their potential use in genetic toxicology, current limitations, and the future work necessary to advance their utility and application. The session culminated with audience-assisted SWOT (strength, weakness, opportunities, and threats) analyses. The summary report described herein is structured similarly. A major conclusion of the workgroup is that while conventional regulatory genetic toxicology testing has served the public well over the last several decades, it does not provide the throughput that has become necessary in modern times, and it does not generate the mechanistic information that risk assessments ideally take into consideration. The high information content assay platforms that were discussed in this session, as well as others under development, have the potential to address aspect(s) of these issues and to meet new expectations in the field of genetic toxicology.
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