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Background Retirement is a major transition in aging, with changes in routine, identity, finances, and social connections, and subsequently mental and physical health. It is possible that the transition through retirement period may increase the risk of loneliness and social isolation. However, the relationship between retirement and loneliness is unclear. We aimed to examine the association between retirement and loneliness and social isolation using a representative sample of older adults. Methods We used survey data from the English Longitudinal Study of Ageing (ELSA), a representative sample of adults over 50 years of age living in private households in England. We analysed waves 4–8 covering the years 2008 to 2017. Loneliness was measured using the UCLA 3-item scale. Social isolation was measured using information on social connections based on previous methods used in ELSA. Binary logistic regression models were used to analyse the effect of retirement on loneliness and social isolation. Results From a total of 3,758 participants, 766 retired between wave 4 and wave 5. Retirement had no effect on short-term loneliness (adjusted odds ratio (aOR): 0.96, 95% CI: 0.77–1.21), but did reduce odds of social isolation (aOR: 0.76, 95% CI: 0.58–0.98) for newly retired individuals when compared to those still working. Further, no association was observed in long-term analysis for either loneliness or social isolation. Conclusions Our findings suggest there is no immediate or long-term association between retirement and loneliness, but there may be a reduction in social isolation in the short-term. Understanding the role retirement plays in the complex relationship between social connection, loneliness and isolation can be used to inform strategies and policies to improve wellbeing in older age.

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.

ObjectivesTo describe the prevalence of sub-optimal monitoring for selected higher-risk medicines in older community-dwelling adults and to evaluate patient characteristics and outcomes associated with sub-optimal monitoring.Study designRetrospective observational study (2011–2015) using historical general practice-based cohort data and linked dispensing data from a national pharmacy claims database.SettingIrish primary care.Participants625 community-dwelling adults aged ≥70 years and prescribed at least one higher-risk medicine during the 5-year study period.Primary and secondary outcome measuresThe primary outcome was the prevalence of sub-optimal laboratory monitoring using a composite measure of published medication monitoring indicators, with a focus on commonly prescribed higher-risk medicines such as diuretics and anticoagulants. Poisson regression was used to assess the patient characteristics associated with sub-optimal monitoring and explanatory variables included the number of medicines, age, sex, deprivation and anxiety/depression symptoms. Logistic regression was used to explore the association between baseline sub-optimal monitoring and the odds of adverse health outcomes (unplanned healthcare utilisation, adverse drug reactions and mortality).ResultsOf 625 participants, the mean age was 77.7 years, 53% were female, the mean number of drugs was 7.3 (SD 3.3) and 499 (79.8%) had ≥1 unmonitored dispensing over 5 years. The number of drugs, deprivation and anxiety/depression symptoms were significantly associated with sub-optimal monitoring, with the strongest association seen for anxiety/depression symptoms (incidence rate ratio: 1.33, 95% CI 1.05 to 1.68). There was a small but significant association between baseline sub-optimal monitoring and emergency department visits at follow-up, but no evidence of an association with unplanned hospital admissions, mortality or adverse drug reactions.ConclusionThe prevalence of sub-optimal medication monitoring was high, and number of drugs, deprivation and anxiety/depression symptoms were significantly associated with sub-optimal monitoring. However, the public health impact of these findings remains uncertain, as there was no clear evidence of an association between sub-optimal monitoring and adverse health outcomes. Further research is needed to evaluate the effect of improved monitoring strategies and the optimal timing for drug monitoring of higher risk medications.

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 misattribution of an adverse drug reaction (ADR) as a symptom or illness can lead to the prescribing of additional medication, referred to as a prescribing cascade. The aim of this systematic review is to identify published prescribing cascades in community‐dwelling adults. A systematic review was reported in line with the PRISMA guidelines and pre‐registered with PROSPERO. Electronic databases (Medline [Ovid], EMBASE, PsycINFO, CINAHL, Cochrane Library) and grey literature sources were searched. Inclusion criteria: community‐dwelling adults; risk‐prescription medication; outcomes‐initiation of new medicine to “treat” or reduce ADR risk; study type‐cohort, cross‐sectional, case‐control, and case‐series studies. Title/ screening, full‐text screening, data extraction, and methodological quality assessment were conducted independently in duplicate. A narrative synthesis was conducted. A total of 101 studies (reported in 103 publications) were included. Study sample sizes ranged from 126 to 11 593 989 participants and 15 studies examined older adults specifically (≥60 years). Seventy‐eight of 101 studies reported a potential prescribing cascade including calcium channel blockers to loop diuretic (n = 5), amiodarone to levothyroxine (n = 5), inhaled corticosteroid to topical antifungal (n = 4), antipsychotic to anti‐Parkinson drug (n = 4), and acetylcholinesterase inhibitor to urinary incontinence drugs (n = 4). Identified prescribing cascades occurred within three months to one year following initial medication. Methodological quality varied across included studies. Prescribing cascades occur for a broad range of medications. ADRs should be included in the differential diagnosis for patients presenting with new symptoms, particularly older adults and those who started a new medication in the preceding 12 months. Prescribing cascades in community dwelling adults: Systematic review.

Current in vitro genotoxicity tests can produce misleading positive results, indicating an inability to effectively predict a compound’s subsequent carcinogenic potential in vivo. Such oversensitivity can incur unnecessary in vivo tests to further investigate positive in vitro results, supporting the need to improve in vitro tests to better inform risk assessment. It is increasingly acknowledged that more informative in vitro tests using multiple endpoints may support the correct identification of carcinogenic potential. The present study, therefore, employed a holistic, multiple-endpoint approach using low doses of selected carcinogens and non-carcinogens (0.001–770 µM) to assess whether these chemicals caused perturbations in molecular and cellular endpoints relating to the Hallmarks of Cancer. Endpoints included micronucleus induction, alterations in gene expression, cell cycle dynamics, cell morphology and bioenergetics in the human lymphoblastoid cell line TK6. Carcinogens ochratoxin A and oestradiol produced greater Integrated Signature of Carcinogenicity scores for the combined endpoints than the “misleading” in vitro positive compounds, quercetin, 2,4-dichlorophenol and quinacrine dihydrochloride and toxic non-carcinogens, caffeine, cycloheximide and phenformin HCl. This study provides compelling evidence that carcinogens can successfully be distinguished from non-carcinogens using a holistic in vitro test system. Avoidance of misleading in vitro outcomes could lead to the reduction and replacement of animals in carcinogenicity testing.

Human exposure to carcinogens occurs via a plethora of environmental sources, with 70–90% of cancers caused by extrinsic factors. Aberrant phenotypes induced by such carcinogenic agents may provide universal biomarkers for cancer causation. Both current in vitro genotoxicity tests and the animal-testing paradigm in human cancer risk assessment fail to accurately represent and predict whether a chemical causes human carcinogenesis. The study aimed to establish whether the integrated analysis of multiple cellular endpoints related to the Hallmarks of Cancer could advance in vitro carcinogenicity assessment. Human lymphoblastoid cells (TK6, MCL-5) were treated for either 4 or 23 h with 8 known in vivo carcinogens, with doses up to 50% Relative Population Doubling (maximum 66.6 mM). The adverse effects of carcinogens on wide-ranging aspects of cellular health were quantified using several approaches; these included chromosome damage, cell signalling, cell morphology, cell-cycle dynamics and bioenergetic perturbations. Cell morphology and gene expression alterations proved particularly sensitive for environmental carcinogen identification. Composite scores for the carcinogens’ adverse effects revealed that this approach could identify both DNA-reactive and non-DNA reactive carcinogens in vitro. The richer datasets generated proved that the holistic evaluation of integrated phenotypic alterations is valuable for effective in vitro risk assessment, while also supporting animal test replacement. Crucially, the study offers valuable insights into the mechanisms of human carcinogenesis resulting from exposure to chemicals that humans are likely to encounter in their environment. Such an understanding of cancer induction via environmental agents is essential for cancer prevention.

Patient and public involvement (PPI) in clinical trials for adults with multimorbidity (multiple long-term conditions) in primary care is essential to ensure research is person-centred. However, PPI is often underreported, limiting understanding of its application and impact. This protocol describes a systematic review examining the uptake, impact and reporting quality of PPI in clinical trials of interventions to improve mental health, clinical or quality-of-life outcomes for adults with multimorbidity in primary care. The review will be guided by the Cochrane Handbook and reported according to PRISMA-P guidelines. Eligible studies include completed and ongoing randomised and non-randomised controlled trials. Multimorbidity is defined as the co-existence of two or more long-term conditions. Electronic databases (MEDLINE, CINAHL, Embase, Cochrane) will be searched from 2019 to update Smith et al. (2021) without language restrictions. Trial registries and grey literature will identify protocols and supplementary data. Inclusion criteria - Population: adults with multimorbidity; Interventions: targeted at this population; Comparison: usual care; Outcomes: mental health, clinical or quality-of-life; Setting: primary or community care. Studies will be included irrespective of whether PPI was reported. Data extraction will capture PPI presence, characteristics, activities, training and acknowledgement. A narrative synthesis will describe reported PPI in clinical trials. Two PPI partners will contribute throughout the review. The protocol is registered with PROSPERO (CRD420251090082). This review will enhance understanding of PPI in trials aiming to improve outcomes for adults with multimorbidity in primary and community care, identify gaps in reporting, and inform future trials to support person-centred research.

IntroductionIntermediate care (IC) is an important destination for older people transitioning from secondary care to home. Inappropriate prescribing is highly prevalent among older people; however, less is known regarding its prevalence within IC. Furthermore, whilst a novel pharmacist case management model has shown improved prescribing appropriateness among older people in IC [1], less is known about predictors of the change observed.MethodsData from older people (≥ 65 years, N = 532) admitted into IC in two Northern Irish healthcare trusts was examined using SPSS version 25. Prevalence of inappropriate prescribing on admission was determined using the Medication Appropriateness Index [2] (MAI) score, assessed by the case management pharmacists. The change in MAI total score from admission to discharge was examined using the Wilcoxon signed-rank test.Multivariate linear regression, robust to data non-normality, was conducted using Mplus 8.1, with MAI score change the outcome variable. Clinical characteristics, pharmacist intervention types and patient demographics were entered as independent variables.ResultsThe majority of participants (89.5%) showed some degree of inappropriate prescribing on admission into IC, indicated by a total MAI score >0. A total of 2377 clinical interventions were recorded for the cohort (M = 4.48, SD = 2.56, range 0-12). A total of 948 medicines were discontinued during IC admission. Total MAI scores reduced significantly from admission (Mdn = 14) to discharge (Mdn = 0) (Z = -18.28, p < .001), with most participants (83.6%) reporting a change. A linear regression model explained 44.2% of the variance in MAI score change, with the change in the number of prescribed medications from admission to discharge the strongest predictor (ß = .584, p < .001). Receiving at least one medication dosage change also positively predicted the magnitude of MAI score change (ß = .206, p < .01).DiscussionInappropriate prescribing is highly prevalent among older people in IC, highlighting the need for medicines optimisation within this care context. The significant reduction in MAI score achieved via pharmacist case management was largely driven by medication discontinuation, however, dosage adjustments also contributed to improved appropriateness.ConclusionsIt cannot be assumed that all medicines have been optimised for the older person prior to transition into intermediate care. Medicines can be successfully optimised by pharmacists within IC via a case management approach.Lessons learnedPharmacist involvement within IC is warranted given the high levels of inappropriate prescribing identified and the significant improvements achieved.LimitationsNo comparison with usual care was made as the service was available to all IC patients.Suggestions for future researchThe healthcare outcomes of participants following case management need to be explored.References1. Miller R. Developments in Practice. Medicines optimisation in older people (MOOP); the journey from pilot to permanent service. Journal of Medicines Optimisation. 2018 Sep;4(2):27.2. Hanlon JT, Schmader KE, Samsa GP, Weinberger M, Uttech KM, Lewis IK, et al. A method for assessing drug therapy appropriateness. Journal of Clinical Epidemiology. 1992 Oct 1;45(10):1045-51.

IntroductionA novel care model, established to address inappropriate prescribing among older people admitted into intermediate care (IC) in Northern Ireland, has shown significant improvements in prescribing appropriateness [1]. Medications are assessed by a case management pharmacist using the Medication Appropriateness Index (MAI) [2]. A patient-specific pharmaceutical care plan is developed, with case management continuing for 30 days post-discharge. To date, the relationship between improved prescribing appropriateness and unplanned hospital readmission following IC discharge has not been examined.MethodsData from older people (≥ 65 years, N=532) admitted into IC in two Northern Irish healthcare trusts was examined using SPSS version 25. The number of unplanned hospital admissions within 30 days, 31-90 days and 0-90 days of IC discharge was examined using Poisson regression. Independent variables including MAI score improvement and clinical intervention types were examined in multivariate analyses, controlling for demographics, medical history and hospital admissions in the previous 12 months. Time to readmission was compared between those who experienced MAI score change and those who did not using Kaplan-Meier survival analysis.ResultsIn total, 115 participants were readmitted following IC discharge. No significant association was observed between MAI score improvement and the number of unplanned readmissions <30 days, 31-90 days and <90 days of IC discharge. Time to readmission was not significantly different for those who experienced a change in total MAI score (Mdn=25) and those who did not (Mdn=28), χ² (1) =.468, p =.494. Patient education and medication dosage alteration were significantly associated with fewer readmissions within 30 days and 31-90 days, respectively. The number of unplanned admissions in the 12 months before IC admission was predictive of the number of readmissions in all three periods (<30, 31-90 and <90 days).DiscussionImproved MAI scores were not associated with unplanned hospital readmissions within 90 days of IC discharge. Individual intervention types showed some significant associations with fewer admissions. Previous hospital admissions, which may serve as a proxy for clinical need, was a consistent predictor of readmissions in the three months following IC discharge.ConclusionsMedicines optimisation in intermediate care has resulted in improved care and drug cost savings [1]. Whilst medicines optimisation was not associated with hospital readmission, elements of the service showed significant associations with fewer admissions.Lessons learnedHospital readmission is multifactorial and may be unavoidable for older people who exhibit greater clinical complexity. Pharmacist involvement within IC may contribute to fewer readmissions for some older people.LimitationsNo random allocation to a control group limit the inferences from identified results.Suggestions for future researchFuture research should identify whether improved prescribing for specific medications show any association with hospital readmission.References1. Miller R. Developments in Practice. Medicines optimisation in older people (MOOP); the journey from pilot to permanent service. Journal of Medicines Optimisation. 2018 Sep;4(2):27.2. Hanlon JT, Schmader KE, Samsa GP, Weinberger M, Uttech KM, Lewis IK, et al. A method for assessing drug therapy appropriateness. Journal of Clinical Epidemiology. 1992 Oct 1;45(10):1045-51.