Complexation of histone deacetylase inhibitor belinostat to Cu(II) prevents premature metabolic inactivation in vitro and demonstrates potent anti-cancer activity in vitro and ex vivo in colon cancer.

PURPOSE: The histone deacetylase inhibitor (HDACi), belinostat, has had limited therapeutic impact in solid tumors, such as colon cancer, due to its poor metabolic stability. Here we evaluated a novel belinostat prodrug, copper-bis-belinostat (Cubisbel), in vitro and ex vivo, designed to overcome the pharmacokinetic challenges of belinostat. METHODS: The in vitro metabolism of each HDACi was evaluated in human liver microsomes (HLMs) using mass spectrometry. Next, the effect of belinostat and Cubisbel on cell growth, HDAC activity, apoptosis and cell cycle was assessed in three colon cancer cell lines. Gene expression alterations induced by both HDACis were determined using RNA-Seq, followed by in silico analysis to identify master regulators (MRs) of differentially expressed genes (DEGs). The effect of both HDACis on the viability of colon cancer patient-derived tumor organoids (PDTOs) was also examined. RESULTS: Belinostat and Cubisbel significantly reduced colon cancer cell growth mediated through HDAC inhibition and apoptosis induction. Interestingly, the in vitro half-life of Cubisbel was significantly longer than belinostat. Belinostat and its Cu derivative commonly dysregulated numerous signalling and metabolic pathways while genes downregulated by Cubisbel were potentially controlled by VEGFA, ERBB2 and DUSP2 MRs. Treatment of colon cancer PDTOs with the HDACis resulted in a significant reduction in cell viability and downregulation of stem cell and proliferation markers. CONCLUSIONS: Complexation of belinostat to Cu(II) does not alter the HDAC activity of belinostat, but instead significantly enhances its metabolic stability in vitro and targets anti-cancer pathways by perturbing key MRs in colon cancer. Complexation of HDACis to a metal ion might improve the efficacy of clinically used HDACis in patients with colon cancer.

Economic evaluation of a collaborative model of pharmaceutical care in an Irish hospital: cost-utility analysis.

Background: A complex, collaborative pharmaceutical care intervention including medication review and reconciliation demonstrated a statistically significant reduction in the prevalence of discharge medication error and improved quality of prescribing for hospitalised adults.  This study sought to assess the cost-effectiveness of this intervention. Methods: A cost-utility analysis was undertaken using a decision-analytic framework. The evaluation was undertaken from the Health Service Executive's perspective, the payer for primary and secondary care settings. Direct costs associated with managing hypothetical harm consequent to intercepted discharge medication error and consequences in terms of quality-adjusted life years loss were key input parameters. Analysis was structured within a decision tree model in Microsoft Excel® populated with consequences as utilities, estimated costs using macro- and micro-costing approaches, and event probabilities generated from the original study. Incremental analysis, one-way and probabilistic sensitivity analyses were performed. Results: The results of analysis for the base-care demonstrated that the intervention dominated standard care with an incremental cost-effectiveness ratio of -€36,537.24/quality-adjusted life year, indicating that the intervention is less costly and more effective. The one-way and probabilistic sensitivity analyses both demonstrated that the intervention dominated standard care. The model was relatively robust to variation in input parameters through one-way sensitivity analysis. The cost of discharge medication error and effect parameters relating to standard care were most sensitive to change. Discussion: The analysis demonstrated the cost-effectiveness of a complex pharmaceutical intervention which will support decision-making regarding implementation. This is the first cost-utility analysis of a complex, collaborative pharmaceutical care intervention, adding to the scant evidence-base in the field.

Potential costs and consequences associated with medication error at hospital discharge: an expert judgement study.

OBJECTIVES: Assessing the cost-effectiveness of complex pharmaceutical care interventions and medication error outcomes is hindered by lack of available data on actual outcomes consequent to errors that were intercepted for patient safety reasons. Expert judgement is an approach to acquire data regarding unknown parameters in an economic model which are otherwise insufficient or not possible to obtain. The aim of this paper is to describe a method to approach this problem using findings from a single intervention study and to calculate the potential costs and consequences associated with discharge medication error. METHODS: Using data from a previous intervention study, the hypothetical consequences of medication error(s) at hospital discharge, in terms of diagnosis, healthcare resource utilisation and impact on health-related quality of life, were identified by expert judgement of anonymised cases. Primary healthcare utilisation costs were derived from published tariffs, inpatient costs were derived by simulation in the hospital discharge activity database test environment and the difference between adjudicated baseline and posterror health state was expressed as quality-adjusted life year (QALY) decrement. RESULTS: Four experts provided judgement on 81 cases. Of these, 75 were judged to have potential clinical consequences. Between 56 and 69 of the 81 cases were variably judged to require remedial healthcare utilisation. The mean calculated cost per case (representing an individual patient), based on all 81 cases, was €1009.58, 95% CI 726.64 to 1585.67. The mean QALY loss was 0.03 (95% CI 0.01 to 0.05). CONCLUSION: An expert judgement process proved feasible and useful to estimate financial cost and QALY loss associated with hospital discharge medication error. These estimates will be employed in model-based economic evaluation. This method could be transferred to other prospective observational patient safety research which seeks to assess value for money of complex interventions.

Evaluating awareness, knowledge and practice of healthcare professionals following implementation of a revised pregnancy prevention programme for isotretinoin in Ireland: A multi-stakeholder cross-sectional study.

PURPOSE: In 2018, following an EU-wide safety review, a revised pregnancy prevention programme (PPP) was introduced for isotretinoin (Roaccutane®). This study aimed to examine awareness, knowledge, and experience implementing the revised isotretinoin PPP in clinical practice across three healthcare professional (HCP) groups in Ireland. METHODS: A cross-sectional study using anonymous online surveys among general practitioners (GPs), community pharmacists, and specialist consultants was undertaken. Descriptive analyses are presented. RESULTS: Across all HCP groups there was high (≥87%) awareness that oral isotretinoin is contraindicated in women of childbearing potential (WCBP) unless the conditions of the PPP are fulfilled, but varying awareness among GPs (54.9%) and community pharmacists (45.9%) that exposure during pregnancy can cause both severe fetal malformations and spontaneous abortions. Implementation of the PPP in clinical practice varied across HCP groups. When initiating isotretinoin in WCBP, 66.7% of specialists and 40.8% of GPs indicated they had considered alternative treatment options, and 71.4% of specialists and 31.6% of GPs reported they first requested a pregnancy test. There was limited provision of the patient reminder card to WCBP, where 26.1% of community pharmacists provide this at each dispensing, while 47.6% of specialists and 11.8% of GPs ensured WCBP had a copy of the card when initiating treatment. Across all HCP groups, there was high (≥81.6%) awareness of the need for urgent consultation and immediate cessation of isotretinoin in the event of an unplanned or suspected pregnancy. CONCLUSIONS: Reinforcement of the provision and utilisation of the isotretinoin patient reminder card may be required, and further targeted education on specific elements of the PPP should be considered for GPs and community pharmacists.

Awareness, knowledge and practice of healthcare professionals following implementation of a Pregnancy Prevention Program for sodium valproate in Ireland: a multi-stakeholder cross-sectional study.

OBJECTIVES: To establish awareness, knowledge, use and experience in practice of a sodium valproate pregnancy prevention program (PPP) in Ireland ("prevent") among three healthcare professional (HCP) groups. METHODS: A cross-sectional study using anonymous online surveys was conducted among general practitioners (GPs), pharmacists, and specialist consultants. Descriptive analyses are presented. RESULTS: HCP response rates were 5.8% for GPs (90/1544), 10.7% for pharmacists (219/2052), and 7.6% for specialists (17/224). Across HCP groups, there was high awareness (>90%) for specialist referral when female valproate patients are planning pregnancy, or become pregnant, but less awareness to refer annually for specialist review. While awareness of a possible teratogenic effect at any stage of pregnancy was high (>80%), most GPs (62.2%, 95% CI: 51.3, 71.9%) and community pharmacists (53.1%, 95% CI: 43.2, 62.8%) were unsure of the magnitude of risk for developmental disorders, while most specialists under-estimated this risk (46.7%, 95% CI: 24.8, 69.9%). Although >70% of the respondents identified valproate to be contraindicated in any woman of childbearing potential unless the conditions of the PPP are fulfilled, experience implementing key elements in practice varied. CONCLUSIONS: Our findings suggest continued effort is needed to ensure optimal implementation of "prevent" into clinical practice in Ireland.

Supporting Law Enforcement Personnel Working with Distressing Material Online.

This study aimed to expand on previous research by gathering international data on key stressors impacting on computer forensic investigators who are exposed to child exploitation material (CEM) as part of their role. Semistructured interviews were conducted with five members of law enforcement (LE) working in this area, from five independent and internationally separated organizations. The results of these interviews were explored using thematic analysis. The three key themes identified were "stressors related to work investigating CEM online," "strategies for mediating stress related to investigating CEM online," and "training to investigate CEM online." Investigators of CEM online may experience stress from several sources, including but not limited to stress from exposure to the material. Other factors such as poor management, high workloads, and limited resources may also result in stress, and these stressors may be mediated to an extent. Recommendations for training, resources, psychological support, and management practices emerged from the research. Such strategies may reduce stress experienced by investigators in this role. This study furthers understanding by conducting an international examination of multiple centers. Identification of common themes and stressors identified by LE personnel in multiple countries can help in the development of international standards and guidelines in training and stress management.

Risk Factors for Social Networking Site Scam Victimization Among Malaysian Students.

Social networking sites (SNSs) can provide cybercriminals with various opportunities, including gathering of user data and login credentials to enable fraud, and directing of users toward online locations that may install malware onto their devices. The techniques employed by such cybercriminals can include clickbait (text or video), advertisement of nonexistent but potentially desirable products, and hoax competitions/giveaways. This study aimed to identify risk factors associated with falling victim to these malicious techniques. An online survey was completed by 295 Malaysian undergraduate students, finding that more than one-third had fallen victim to SNS scams. Logistic regression analysis identified several victimization risk factors including having higher scores in impulsivity (specifically cognitive complexity), using fewer devices for SNSs, and having been on an SNS for a longer duration. No reliable model was found for vulnerability to hoax valuable gift giveaways and "friend view application" advertising specifically, but vulnerability to video clickbait was predicted by lower extraversion scores, higher levels of openness to experience, using fewer devices, and being on an SNS for a longer duration. Other personality traits were not associated with either overall victimization susceptibility or increased risk of falling victim to the specific techniques. However, age approached significance within both the video clickbait and overall victimization models. These findings suggest that routine activity theory may be particularly beneficial in understanding and preventing SNSs scam victimization.

Language in Online Dating Texts: Trait Identification, Homophily, and their Effect on Attraction.

Research has indicated that online daters may pick up on language cues connected to personality traits in online dating profile texts, and act upon those cues. This research seeks to investigate the level of accuracy of detection of personality in dating profile texts, and the extent to which perceived or actual similarity of personality has an effect on attractiveness of the author. An online survey was conducted collecting the Ten Item Personality Inventory (TIPI) for each participant and text author, a peer-report TIPI score by participants for each text author, and an attractiveness rating on a Likert scale for each author. Participants correctly identified Extraversion, though the effect size was small. Contrary to the hypotheses, participants preferred texts when written by an author with a personality they perceived as dissimilar to their own, specifically in Openness and Conscientiousness, and no relationship was found between actual similarity of personality and attractiveness. Online daters may choose partners with complementary or desirable traits rather than similar traits, or other factors in attraction may be more salient in the initial stages of determining attraction.

A comparison of text and technology based training tools to improve cognitive skills in older adults.

Research has indicated that use of cognitive skills training tools can produce positive benefits with older adults. However, little research has compared the efficacy of technology-based interventions and more traditional, text-based interventions which are also available. This study aimed to investigate cognitive skills improvements experienced by 40 older adults using cognitive skills training tools. A Solomon 4 group design was employed to determine which intervention demonstrated the greatest improvement. Participants were asked to use the interventions for 5-10 minutes per day, over a period of 60 days. Pre and post-tests consisted of measures of numerical ability, self-reported memory and intelligence. Following training, older adults indicated significant improvements on numerical ability and intelligence regardless of intervention type. No improvement in selfreported memory was observed. This research provides a critical appraisal of brain training tools and can help point the way for future improvements in the area. Brain training improvements could lead to improved quality of life, and perhaps, have financial and independent living ramifications for older adults.