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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.

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.

Stalled replication forks can be restarted and repaired by RAD51-mediated homologous recombination (HR), but HR can also perform post-replicative repair after bypass of the obstacle. Bulky DNA adducts are important replication-blocking lesions, but it is unknown whether they activate HR at stalled forks or behind ongoing forks. Using mainly BPDE-DNA adducts as model lesions, we show that HR induced by bulky adducts in mammalian cells predominantly occurs at post-replicative gaps formed by the DNA/RNA primase PrimPol. RAD51 recruitment under these conditions does not result from fork stalling, but rather occurs at gaps formed by PrimPol re-priming and resection by MRE11 and EXO1. In contrast, RAD51 loading at double-strand breaks does not require PrimPol. At bulky adducts, PrimPol promotes sister chromatid exchange and genetic recombination. Our data support that HR at bulky adducts in mammalian cells involves post-replicative gap repair and define a role for PrimPol in HR-mediated DNA damage tolerance. Bulky DNA adducts are important replication-blocking lesions. Here the authors reveal that homologous recombination at bulky adducts in mammalian cells involves post-replicative gap repair in a PrimPol dependent manner.

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.

Smoke from southern Africa blankets the southeastern Atlantic Ocean from June to October, producing strong and competing aerosol radiative effects. Smoke effects on the transition between overcast stratocumulus and scattered cumulus clouds are investigated along a Lagrangian (air-mass-following) trajectory in regional climate and large eddy simulation models. Results are compared with observations from three recent field campaigns that took place in August 2017: ObseRvations of Aerosols above CLouds and their intEractionS (ORACLES), CLouds and Aerosol Radiative Impacts and Forcing: Year 2017 (CLARIFY), and Layered Atlantic Smoke Interactions with Clouds (LASIC). The case study is set up around the joint ORACLES–CLARIFY flight that took place near Ascension Island on 18 August 2017. Smoke sampled upstream on an ORACLES flight on 15 August 2017 likely entrained into the marine boundary layer later sampled during the joint flight. The case is first simulated with the WRF-CAM5 regional climate model in three distinct setups: (1) FireOn, in which smoke emissions and any resulting smoke–cloud–radiation interactions are included; (2) FireOff, in which no smoke emissions are included; (3) RadOff, in which smoke emissions and their microphysical effects are included but aerosol does not interact directly with radiation. Over the course of the Lagrangian trajectory, differences in free tropospheric thermodynamic properties between FireOn and FireOff are nearly identical to those between FireOn and RadOff, showing that aerosol–radiation interactions are primarily responsible for the free tropospheric effects. These effects are non-intuitive: in addition to the expected heating within the core of the smoke plume, there is also a “banding” effect of cooler temperature (∼1–2 K) and greatly enhanced moisture (>2 g kg−1) at the plume top. This banding effect is caused by a vertical displacement of the former continental boundary layer in the free troposphere in the FireOn simulation resulting from anomalous diabatic heating due to smoke absorption of sunlight that manifests primarily as a few hundred meters per day reduction in large-scale subsidence over the ocean. A large eddy simulation (LES) is then forced with free tropospheric fields taken from the outputs for the WRF-CAM5 FireOn and FireOff runs. Cases are run by selectively perturbing one variable (e.g., aerosol number concentration, temperature, moisture, vertical velocity) at a time to better understand the contributions from different indirect (microphysical), “large-scale” semi-direct (above-cloud thermodynamic and subsidence changes), and “local” semi-direct (below-cloud smoke absorption) effects. Despite a more than 5-fold increase in cloud droplet number concentration when including smoke aerosol concentrations, minimal differences in cloud fraction evolution are simulated by the LES when comparing the base case with a perturbed aerosol case with identical thermodynamic and dynamic forcings. A factor of 2 decrease in background free tropospheric aerosol concentrations from the FireOff simulation shifts the cloud evolution from a classical entrainment-driven “deepening–warming” transition to trade cumulus to a precipitation-driven “drizzle-depletion” transition to open cells, however. The thermodynamic and dynamic changes caused by the WRF-simulated large-scale adjustments to smoke diabatic heating strongly influence cloud evolution in terms of both the rate of deepening (especially for changes in the inversion temperature jump and in subsidence) and in cloud fraction on the final day of the simulation (especially for the moisture “banding” effect). Such large-scale semi-direct effects would not have been possible to simulate using a small-domain LES model alone.

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.

Background Paediatric traumatic brain injury (TBI) is recognised to have significant longer-term neurocognitive effects. Childhood is a time of high risk for head injury. Functional recovery is variable with a combination of any or all of physical, cognitive and emotional impairment. Immune activation and alteration in cytokine levels are present following TBI which may differ from adults. Methods Pro- and anti-inflammatory cytokines including Interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, IL-17A, Tumor Necrosis Factor (TNF)-α and Interferon (IFN)-γ were examined at baseline and following in vitro treatment with endotoxin of whole blood, in the following children: severe TBI (sTBI: initial Glasgow coma scale(GCS) ≤ 8), mild TBI (mTBI; GCS 14/15) at 0-4d and at 10-14d post-TBI and compared to healthy age-matched controls. Results The study enrolled 208 children, including 110 with TBI cohort ( n  = 104 mild; 6 severe) and controls ( n  = 98). At baseline all children with TBI had increased IL-6. The mTBI group had significantly increased IFN-γ versus controls. In sTBI at baseline, IFN-γ was decreased compared to controls. At baseline IL-8, IL-10, IL-17A, and TNF-α were decreased in mTBI compared to controls. This persisted at 2 week post-mTBI. The AUC for detecting mTBI was 0.801 CI (0.73–086) using IL6/IL10 ratio. mTBI showed a greater fold change in IL-8 and TNF-α in response to endotoxin stimulation, a response that persisted at 2 weeks. Children with sTBI did not have a significant IL-6 response to endotoxin, but did show an increase in IL-17A. Conclusion Children with all TBI including mTBI show altered cytokine profiles and altered endotoxin responses. Although cytokines increased in sTBI especially in response to endotoxin, suppressed responses were found in mTBI coupled with persistent immune dysfunction post-injury.

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.