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The blood-brain barrier (BBB) controls the movement of molecules into and out of the central nervous system (CNS). Since a functional BBB forms by mouse embryonic day E15.5, we reasoned that gene cohorts expressed in CNS endothelial cells (EC) at E13.5 contribute to BBB formation. In contrast, adult gene signatures reflect BBB maintenance mechanisms. Supporting this hypothesis, transcriptomic analysis revealed distinct cohorts of EC genes involved in BBB formation and maintenance. Here, we demonstrate that epigenetic regulator’s histone deacetylase 2 (HDAC2) and polycomb repressive complex 2 (PRC2) control EC gene expression for BBB development and prevent Wnt/β-catenin (Wnt) target genes from being expressed in adult CNS ECs. Low Wnt activity during development modifies BBB genes epigenetically for the formation of functional BBB. As a Class-I HDAC inhibitor induces adult CNS ECs to regain Wnt activity and BBB genetic signatures that support BBB formation, our results inform strategies to promote BBB repair.

Mutations in genes encoding transcription factors inactivate or generate ectopic activities to instigate pathogenesis. By disrupting hematopoietic stem/progenitor cells, GATA2 germline variants create a bone marrow failure and leukemia predisposition, GATA2 deficiency syndrome, yet mechanisms underlying the complex phenotypic constellation are unresolved. We used a GATA2-deficient progenitor rescue system to analyze how genetic variation influences GATA2 functions. Pathogenic variants impaired, without abrogating, GATA2-dependent transcriptional regulation. Variants promoted eosinophil and repressed monocytic differentiation without regulating mast cell and erythroid differentiation. While GATA2 and T354M required the DNA-binding C-terminal zinc finger, T354M disproportionately required the N-terminal finger and N terminus. GATA2 and T354M activated a CCAAT/Enhancer Binding Protein-e (C/EBPe) enhancer, creating a feedforward loop operating with the T-cell Acute Lymphocyte Leukemia-1 (TAL1) transcription factor. Elevating C/EBPe partially normalized hematopoietic defects of GATA2-deficient progenitors. Thus, pathogenic germline variation discriminatively spares or compromises transcription factor attributes, and retaining an obligate enhancer mechanism distorts a multilineage differentiation program. [ABSTRACT FROM AUTHOR]

Rationale: Alcohol-intoxication is implicated in negative social behaviours, however the mechanisms underlying this relationship are poorly understood. Impaired emotion perception following alcohol consumption may partially account for this link, however limited methodology in prior studies undermines the efficacy of this explanation., Objectives: The current study investigated the effect of acute moderate-dose alcohol-intoxication on basic and compound emotion perception abilities using contextualised video vignettes. Self-appraisals of performance accuracy were also investigated., Methods: Sixty-eight participants consumed a beverage containing either (a) an alcohol dose calculated to achieve a BrAC of 0.08%, or (b) a placebo. The Complex Audio-Visual Emotion Assessment Task (CAVEAT) was used to assess emotion perception ability. Anticipatory performance accuracy and emergent confidence judgements were made on the CAVEAT., Results: There were no significant between-group differences on emotion perception ability and emergent confidence judgements. However, anticipatory performance accuracy was more aligned to actual performance in the alcohol intoxication group compared to the placebo group., Conclusions: Overall, these results suggest that (1) deficits in perception of facial emotional expressions following alcohol intoxication may not be as pronounced as originally suspected; and (2) the questioning of performance accuracy may prompt intoxicated individuals to anticipate poorer emotion perception performance, which may lead to better monitoring of-and improvements in-task performance., Competing Interests: Declarations. Conflict of interest: On behalf of all authors, the corresponding author states that there is no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Opioids kill more people than any other drug. Naloxone is an opioid antagonist which can be distributed in take-home 'kits' for peer administration (take-home naloxone)., Aim: To determine the feasibility of carrying out a definitive randomised controlled trial of take-home naloxone in emergency settings., Design: We used Welsh routine data (2015-21) to test the feasibility of developing a discriminant function to identify people at high risk of fatal opioid overdose. We carried out a cluster randomised controlled trial and qualitative study to examine experiences of service users and providers. We assessed feasibility of intervention and trial methods against predetermined progression criteria related to: site sign-up, staff trained, identification of eligible patients, proportion given kits, identification of people who died of opioid poisoning, data linkage and retrieval of outcomes., Setting: This study was carried out in the emergency environment; sites comprised an emergency department and associated ambulance service catchment area., Participants: At intervention sites, we invited emergency department clinicians and paramedics to participate. We recruited adult patients who arrived at the emergency department or were attended to by ambulance paramedics for a problem related to opioid use with capacity to consent to receiving the take-home naloxone and related training., Interventions: Usual care comprised basic life support plus naloxone by paramedics or emergency department staff. The take-home naloxone intervention was offered in addition to usual care, with guidance for recipients on basic life support, the importance of calling the emergency services, duration of effect, safety and legality of naloxone administration., Discriminant Function: With low numbers of opioid-related deaths (1105/3,227,396) and a high proportion having no contact with health services in the year before death, the predictive link between death and opioid-related healthcare events was weak. Logistic regression models indicated we would need to monitor one-third of the population to capture 75% of the decedents from opioid overdose in 1-year follow-up., Randomised Controlled Trial: Four sites participated in the trial and 299 of 687 (44%) eligible clinical staff were trained. Sixty take-home naloxone kits were supplied to patients during 1-year recruitment. Eligible patients were not offered take-home naloxone kits 164 times: 'forgot' ( n  = 136); 'too busy' ( n  = 15); suspected intentional overdose ( n  = 3)., Qualitative Interviews: Service users had high levels of knowledge about take-home naloxone. They were supportive of the intervention but noted concerns about opioid withdrawal and resistance to attending hospital for an overdose. Service providers were positive about the intervention but reported barriers including difficulty with consenting and training high-risk opioid users., Health Economics: We were able to calculate costs to train staff at three sites (£40 per AS and £17 in Site 1 ED). No adverse events were reported. Progression criteria were not met - fewer than 50% of eligible staff were trained, fewer than 50% of eligible patients received the intervention and outcomes were not retrieved within reasonable timescales., Future Work: The take-home naloxone intervention needs to be developed and evaluated in emergency care settings, with appropriate methods., Limitations: The Take-home naloxone Intervention Multicentre Emergency setting study was interrupted by coronavirus disease., Conclusions: This study did not meet progression criteria for intervention or trial methods feasibility, so outcomes were not followed up and a fully powered trial is not planned., Trial Registration: This trial is registered as ISRCTN13232859., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/91/04) and is published in full in Health Technology Assessment ; Vol. 28, No. 74. See the NIHR Funding and Awards website for further award information.

Background: Disability is a key factor related to self-concept change following a Multiple Sclerosis (MS) diagnosis. Psychosocial factors (e.g., social integration, marital support) are also associated with changing self-concept in people with MS (pwMS). What remains unclear however, is whether psychosocial factors account for the relationship between disability and self-concept change. The current study aimed to investigate the potential mediation effect of Health-Related Quality of Life (HRQoL) on the relationship between disability and self-concept change in pwMS, and whether relationship satisfaction is a moderator of the mediated relationship., Method: Nine hundred and ninety-five pwMS (79.5 % female; Age M = 59.72 years, SD = 11.15) completed measures of disability, HRQoL, and self-concept change. Of these participants, seven hundred and twenty-six pwMS who indicated they were currently in a relationship also completed a measure of relationship satisfaction., Results: A moderated mediation (conditional process) analysis indicated that the relationship between disability and self-concept change was partially mediated by HRQoL. A further parallel mediation found that across the eight subdomains of HRQoL, only participants' reported levels of 'relationships' and 'coping' significantly mediated the relationship between disability and self-concept change. However, for those participants in a relationship, relationship satisfaction did not moderate any mediation effects., Conclusion: The findings highlight the role that perceptions of HRQoL in some domains may have in explaining the relationship between disability and self-concept change. Further research is needed to explicate the causal direction of these relationships through longitudinal studies., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Opioids kill more people than any other class of drug. Naloxone is an opioid antagonist which can be distributed in kits for peer administration. We assessed the feasibility of implementing a Take-home Naloxone (THN) intervention in emergency settings, as part of designing a definitive randomised controlled trial (RCT)., Methods: We undertook a clustered RCT on sites pairing UK Emergency Departments (ED) and ambulance services. At intervention sites, we recruited emergency healthcare practitioners to supply THN to patients presenting with opioid overdose or related condition, with recruitment across 2019-2021. We assessed feasibility of intervention implementation against four predetermined progression criteria covering site sign up and staff training; identification of eligible patients; issue of THN kits and Serious Adverse Events., Results: At two intervention sites, randomly selected from 4, 299/687 (43.5%) clinical staff were trained (ED1 = 107, AS1 = 121, ED2 = 25, AS2 = 46). Sixty THN kits were supplied to eligible patients (21.7%) (n: ED1 = 36, AS1 = 4, ED2 = 16, AS2 = 4). Across sites, kits were not issued to eligible patients on a further 164 occasions, with reasons reported including: staff forgot (n = 136), staff too busy (n = 15), and suspected intentional overdose (n = 3), no kit available (n = 2), already given by drugs nurse (n = 4), other (n = 4). Staff recorded 626 other patients as ineligible but considered for inclusion, with reasons listed as: patient admitted to hospital (n = 194), patient absconded (n = 161) already recruited (n = 64), uncooperative or abusive (n = 55), staff not trained (n = 43), reduced consciousness level (n = 41), lack of capacity (n = 35), patient in custody (n = 21), other (n = 12). No adverse events were reported., Conclusion: Staff and patient recruitment were low and varied widely by site. This feasibility study did not meet progression criteria; a fully powered RCT is not planned., Trial Registration: ISRCTN13232859 (Registered 16/02/2018)., (© 2024. The Author(s).)

Introduction: Peer workers operating within health care settings can offer unique perspectives based on their own lived experience. Within alcohol and other drug (AOD) rehabilitation services, the potential value of peer work is becoming increasingly recognised. This qualitative study aimed to evaluate a newly implemented peer worker program located across three rehabilitation services in Tasmania, Australia., Methods: Online interviews were conducted with eight clients, seven peer workers, and five non-peer worker employees with varied experience with peer worker programs. All interviews were audio-recorded and transcribed verbatim., Results: Guided by an overarching exploratory-descriptive methodological framework, thematic analysis generated three overarching themes: 1) Enhancing and supporting client experiences (what peer workers did in their role to improve client experiences, 2) Changing experiences with AOD rehabilitation (the unique benefits and changes that peer work brings to AOD rehabilitation services) and 3) Finding organizational value (how defining peer work and the feasibility of the peer worker role was challenged by different organizational factors). Overall, peer work was viewed as a positive addition to all rehabilitation services that was able to enhance client experiences through various mechanisms, such as by sharing their own stories, assisting with understanding, and creating safety. Peer work was also able to create change in AOD services, by instilling hope and reducing stigma. However, ongoing challenges with defining the peer worker role in a way that offers organizational recognition and financial security remain., Conclusion: Peer workers offer a unique and valuable perspective when working within rehabilitation services. Through their own lived experience peer workers were able to support clients and assist them in their recovery. These findings highlight the potential benefit of peer work programs within AOD rehabilitation services., Competing Interests: Declaration of competing interest This article presents a qualitative evaluation of a peer worker program implemented by the Drug Education Network (DEN). In the interest of full transparency, we disclose the following potential conflicts of interest: MD is a paid staff member of DEN, who was involved in the implementation of the program. Their firsthand experience with the program's implementation provided valuable insights and their involvement provided the additional logistical resources needed to conduct the research across the state, yet we acknowledge the potential for a conflict of interest. To mitigate these, this author was not involved in the screening or interviewing of any organizational non-peer worker employees or peer workers that they may have had previous contact with. In addition, MD followed a pre-defined interview schedule developed by HE, and all interviews were reviewed by the chief investigator. We affirm that their role did not compromise the objective evaluation of the program. AM is a senior academic at the University of Tasmania and a voluntary Board member of DEN. While their involvement with DEN may pose a perceived conflict, this author was not directly involved in the implementation of the program, or in the data collection and initial data analysis. HE was the lead investigator for this evaluation study and has no direct affiliation with DEN, ensuring an independent perspective in the research process and analysis. Despite these affiliations, all procedures and analyses were conducted with the utmost integrity and objectivity. The findings and conclusions presented in this article are the result of rigorous and unbiased research practices., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Climate change is leading to more extreme heat events in temperate climates that typically have low levels of preparedness. Our objective was to describe the characteristics, treatments, and outcomes of adults presenting to hospitals with heatstroke during BC's 2021 heat dome., Methods: We conducted a review of consecutive adults presenting to 7 hospitals in BC's Lower Mainland. We screened the triage records of all patients presenting between June 25th and 30th, 2021 for complaints related to heat, and reviewed the full records of those who met heatstroke criteria. Our primary outcome was in-hospital mortality. We used Mann-Whitney U tests and logistic regression to investigate associations between patient and treatment factors and mortality., Results: Among 10,247 consecutive presentations to urban hospitals during the extreme heat event, 1.3% (139; 95% confidence intervals [CI] 1.1-1.6%) met criteria for heatstroke. Of heatstroke patients, 129 (90.6%) were triaged into the two highest acuity levels. Patients with heatstroke had a median age of 84.4 years, with 122 (87.8%) living alone, and 101 (84.2%) unable to activate 911 themselves. A minority (< 5, < 3.6%) of patients presented within 48 h of the onset of extreme heat. Most patients (107, 77.0%) required admission, and 11.5% (16) died in hospital. Hypotension on presentation was associated with mortality (odds ratio [OR] 5.3)., Interpretation: Heatstroke patients were unable to activate 911 themselves, and most presented with a 48-h delay. This delay may represent a critical window of opportunity for pre-hospital and hospital systems to prepare for the influx of high-acuity resource-intensive patients., (© 2023. The Author(s).)