Disagreement concerning atopic dermatitis subtypes between an English prospective cohort (ALSPAC) and linked electronic health records.

BACKGROUND: Subtypes of atopic dermatitis (AD) have been derived from the Avon Longitudinal Study of Parents and Children (ALSPAC) based on presence and severity of symptoms reported in questionnaires (Severe-Frequent, Moderate-Frequent, Moderate-Declining, Mild-Intermittent, Unaffected/Rare). Good agreement between ALSPAC and linked electronic health records (EHRs) would increase trust in the clinical validity of these subtypes and allow inferring subtypes from EHRs alone, which would enable their study in large primary care databases. OBJECTIVES: 1. Explore if presence and number of AD records in EHRs agrees with AD symptom and severity reports from ALSPAC; 2. Explore if EHRs agree with ALSPAC-derived AD subtypes; 3. Construct models to classify ALSPAC-derived AD subtype using EHRs. METHODS: We used data from the ALSPAC prospective cohort study from 11 timepoints until age 14 years (1991-2008), linked to local general practice EHRs. We assessed how far ALSPAC questionnaire responses and derived subtypes agreed with AD as established in EHRs using different AD definitions (e.g., diagnosis and/or prescription) and other AD-related records. We classified AD subtypes using EHRs, fitting multinomial logistic regression models tuning hyperparameters and evaluating performance in the testing set (ROC AUC, accuracy, sensitivity, and specificity). RESULTS: 8,828 individuals out of a total 13,898 had both been assigned an AD subtype and had linked EHRs. The number of AD-related codes in EHRs generally increased with severity of AD subtype, however not all with the Severe-Frequent subtypes had AD in EHRs, and many with the Unaffected/Rare subtype did have AD in EHRs. When predicting ALSPAC AD subtype using EHRs, the best tuned model had ROC AUC of 0.65, sensitivity of 0.29 and specificity of 0.83 (both macro averaged); when different sets of predictors were used, individuals with missing EHR coverage excluded, and subtypes combined, sensitivity was not considerably improved. CONCLUSIONS: ALSPAC and EHRs disagreed not just on AD subtypes, but also on whether children had AD or not. Researchers should be aware that individuals considered as having AD in one source may not be considered as having AD in another.

γ-Secretase Modulator BPN15606 Reduced Aß42 and Aß40 and Countered Alzheimer-Related Pathologies in a Mouse Model of Down Syndrome.

OBJECTIVES: Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS-AD. How the increased APP gene dose acts and which APP products are responsible for DS-AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of γ-secretase modulators that promote γ-site cleavages by the γ-secretase complex, resulting in lower levels of the Aß42 and Aß40 peptides. METHODS: Ts65Dn mice, which serve as a model of DS, were treated via oral gavage with 10 mg/kg/weekday of BPN15606 (a potent and novel pyridazine-containing γ-secretase modulators). Treatment started at 3 months-of-age and lasted for 4 months. RESULTS: Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Aß40 and Aß42 in the cortex and hippocampus; it had no effect on full-length APP or its C-terminal fragments in either 2 N or Ts65Dn mice. Importantly, the levels of total amyloid-ß were not impacted, pointing to BPN15606-mediated enhancement of processivity of γ-secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits. INTERPRETATION: Our findings point to the involvement of increased levels of Aß42 and/or Aß40 in contributing to several molecular and cognitive traits associated with DS-AD. They speak to increased dosage of the APP gene acting through heightened levels of Aß42 and/or Aß40 as supporting pathogenesis. These findings further the interest in the potential use of γ-secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024.

Intersection of gambling with smoking and alcohol use in Great Britain: a cross-sectional survey in October 2022.

OBJECTIVES: Gambling is associated with cigarette smoking and alcohol consumption. We explored the intersection of gambling across all risk levels of harm with smoking and alcohol use among adults in Great Britain. DESIGN: A nationally representative cross-sectional survey in October 2022. SETTING: Great Britain. PARTICIPANTS: A weighted total of 2398 adults (18+ years). OUTCOME MEASURES: We examined the prevalence of past-year gambling and, among those reporting gambling, assessed the associations between the outcome of any risk of harm from gambling (scoring >0 on the Problem Gambling Severity Index) and the binary predictor variables of current cigarette smoking and higher risk alcohol consumption (AUDIT-C score≥4). We also explored data on weekly expenditure on gambling with smoking and alcohol use among those categorised at any-risk of harm from gambling. RESULTS: Overall, 43.6% (95% CI 41.2% to 45.9%) of adults gambled in the past year. Among these, 7.3% (95% CI 5.3% to 9.3%) were classified at any-risk of harm from gambling, 16.0% (95% CI 13.2% to 18.8%) were currently smoking and 40.8% (95% CI 37.2% to 44.4%) were drinking at increasing and higher risk levels. There were no associations between any risk of harm from gambling and current smoking (OR adjusted=0.80, 95% CI 0.35 to 1.66) or drinking at increasing and higher risk levels (OR adjusted=0.94, 95% CI 0.52 to 1.69), respectively. Analyses using Bayes factors indicated that these data were insensitive to distinguish no effect from a range of associations (OR=95% CI 0.5 to 1.9). The mean weekly spend on gambling was £7.69 (95% CI £5.17 to £10.21) overall, £4.80 (95% CI £4.18 to £5.43) among those classified as at no risk and £45.68 (95% CI £12.07 to £79.29) among those at any risk of harm from gambling. CONCLUSIONS: Pilot data in a population-level survey on smoking and alcohol use yielded similar estimates to other population-level surveys on gambling participation and at-risk gambling. Further data are needed to elucidate the intersections more reliably between gambling, smoking and alcohol use and inform population-level approaches to reduce harm.

The Canadian Breast Cancer Symposium 2023 Meeting Report.

On 15-16 June 2023, healthcare professionals and breast cancer patients and advocates from across Canada met in Toronto, Ontario, for the 2023 Canadian Breast Cancer Symposium (CBSC.). The CBSC. is a national, multidisciplinary event that occurs every 2 years with the goal of developing a personalized approach to the management of breast cancer in Canada. Experts provided state-of-the-art information to help optimally manage breast cancer patients, including etiology, prevention, diagnosis, experimental biology, and therapy of breast cancer and premalignant breast disease. The symposium also had the objectives of increasing communication and collaboration among breast cancer healthcare providers nationwide and providing a comprehensive and real-life review of the many facets of breast cancer. The sessions covered the patient voice, the top breast cancer papers from different disciplines in 2022, artificial intelligence in breast cancer, systemic therapy updates, the management of central nervous system metastases, multidisciplinary management of ductal carcinoma in situ, special populations, optimization-based individual prognostic factors, toxicity management of novel therapeutics, survivorship, and updates in surgical oncology. The key takeaways of these sessions have been summarized in this conference report.

Neoadjuvant chemotherapy for triple-negative and Her2 +ve breast cancer: striving for the standard of care.

PURPOSE: Neoadjuvant chemotherapy (NAC) for triple-negative (TN) and Her2-positive (HER2) breast cancers is supported by international guidelines as it can decrease extent of surgery, provide prognostic information, and allow response-driven adjuvant therapies. Our goal was to describe practice patterns for patients with TN and HER2-positive breast cancer and identify the factors associated with the receipt of NAC versus surgery as initial treatment. METHODS: A retrospective population-based cohort study of adult women diagnosed with stage I-III TN or HER2-positive breast cancer (2012-2020) in Ontario was completed using linked administrative datasets. The primary outcome was NAC as first treatment. The association between NAC and patient, tumor, and practice-related factors was examined using multivariable logistic regression models. RESULTS: Of 14,653 patients included, 23.9% (n = 3500) underwent NAC as first treatment. Patients who underwent NAC were more likely to be younger and have larger tumors, node-positive disease, and stage 3 disease. Of patients who underwent surgery first, 8.8% were seen by a medical oncologist prior to surgery. On multivariable analysis, increasing tumor size (T2 vs T1/T0: 2.75 (2.31-3.28)) and node-positive (N1 vs N0: OR 3.54 (2.92-4.30)) disease were both associated increased odds of receiving NAC. CONCLUSION: A considerable proportion of patients with TN and HER2-positive breast cancer do not receive NAC as first treatment. Of those, most were not assessed by both a surgeon and medical oncologist prior to initiating therapy. This points toward potential gaps in multidisciplinary assessment and disparities in receipt of guideline-concordant care.

Lymphovenous Bypass for Immediate Lymphatic Reconstruction in Breast Cancer Patients Undergoing Axillary Lymph Node Dissection: Minimizing the Risk of Upper Extremity Lymphedema.

BACKGROUND: Studies have shown a significant reduction in breast cancer-related lymphedema (BCRL) rates in patients undergoing complete axillary lymph node dissection (cALND) combined with immediate lymphatic reconstruction (ILR) using lymphovenous bypass (LVB).The purpose of this study was to determine if ILR with LVB at the time of cALND results in a decreased incidence of BCRL and its impact on patient quality of life (QOL). METHODS: In this prospective cohort study, patients ≥ 18 years requiring cALND underwent ILR from 2019 to 2021. The primary outcome was bilateral upper limb volumes measured by Brørson's truncated cone formula and the Pero-System (3D Körper Scanner). The secondary outcome was QOL measured by the Lymphedema Quality of Life (LYMQOL) arm patient-reported outcome measurement. RESULTS: Forty-two patients consented to ILR using LVB. ILR was completed in 41 patients with a mean of 1.9 ± 0.9 lymphovenous anastomosis performed. Mean age of patients was 52.4 ± 10.5 years with a mean body mass index of 27.5 ± 4.9 kg/m2. All patients (n = 39, 100%) received adjuvant therapy after ILR. Mean follow-up was 15.2 ± 5.1 months. Five patients met criteria for lymphedema throughout the duration of the study (12.8%), with two patients having resolution, with an overall incidence of 7.7% by the end of the study period. Patients with lymphedema were found to have statistically significant lower total LYMQOL values at 18 months (8.44 ± 1.17 vs. 3.23 ± 0.56, p < 0.001). A mean increase of 0.73 ± 3.5 points was observed for overall QOL average for upper limb function at 18 months compared with 3 months (t = 0.823, p = 0.425). CONCLUSION: This study showed an incidence of 7.7% lymphedema development throughout the duration of study. We also showed that ILR has the potential to reduce the significant long-term adverse outcomes of lymphedema and improve QOL for patients undergoing cALND.

Hospital Acquired Venous Thromboembolism: A Preventability Assessment.

Background: The American Heart Association has a call to action to reduce hospital acquired venous thromboembolism (HA-VTE) by 20% by the year 2030. There is increasing recognition that quality improvement initiatives for VTE reduction should focus on reducing potentially preventable HA-VTE. The objective of our study was to determine what proportion of HA-VTE events are potentially preventable. Methods: This was a retrospective, single center pilot study of 50 patients with HA-VTE. Seven preventability factors were identified with a focus on VTE prescription and administration. Data were extracted through chart review using a systematic data collection form. The primary endpoint was the proportion of patients with potentially preventable HA-VTE. Descriptive statistics were used. Results: The median age was 66 years with an admission VTE risk level of moderate-high in 94%. Potentially preventable HA-VTE was found in 40% of cases. Missed doses occurred in 29.8% with a median of 2 missed doses and a range of 1 to 20. Patient refusal was the most common reason for missed doses in 71%. Delays in initiation occurred in 12.7%. Sixty percent of those on mechanical prophylaxis only had nonadherence. Conclusion: Forty percent of HA-VTE cases were potentially preventable. Missed doses was the most common preventability factor identified with patient refusal accounting for most missed doses.

Online behavioural interventions for children and young people with eczema: a quantitative evaluation.

BACKGROUND: Two online behavioural interventions (one website for parents/carers of children with eczema; and one for young people with eczema) have been shown in randomised controlled trials to facilitate a sustained improvement in eczema severity. AIM: To describe intervention use and examine potential mediators of intervention outcomes and contextual factors that may influence intervention delivery and outcomes. DESIGN AND SETTING: Quantitative process evaluation in UK primary care. METHOD: Parents/carers and young people were recruited through primary care. Intervention use was recorded and summarised descriptively. Logistic regression explored sociodemographic and other factors associated with intervention engagement. Mediation analysis investigated whether patient enablement (ability to understand and cope with health issues), treatment use, and barriers to adherence were mediators of intervention effect. Subgroup analysis compared intervention effects among pre-specified participant subsets. RESULTS: A total of 340 parents/carers and 337 young people were recruited. Most parents/carers (87%, n = 148/171) and young people (91%, n = 153/168) in the intervention group viewed the core introduction by 24 weeks. At 24 weeks, users had spent approximately 20 minutes on average on the interventions. Among parents/carers, greater intervention engagement was associated with higher education levels, uncertainty about carrying out treatments, and doubts about treatment efficacy at baseline. Among young people, higher intervention use was associated with higher baseline eczema severity. Patient enablement (the ability to understand and cope with health issues) accounted for approximately 30% of the intervention effect among parents/carers and 50% among young people. CONCLUSION: This study demonstrated that positive intervention outcomes depended on a modest time commitment from users. This provides further support that the wider implementation of Eczema Care Online is justified.

Development of an intervention for reducing infant bathing frequency.

BACKGROUND: Bathing babies less frequently and intensively in the first six months of life may prevent eczema, but this has not yet been definitively tested in a randomised controlled trial. Such a trial would require evidence-based support to help parents engage with a minimal bathing routine. The present study reports the development of this support. METHODS: We adopted a four-stage design process: (i) Pregnant women and their families (n = 31) were interviewed to ascertain key barriers and facilitators towards following the minimal bathing intervention. (ii) These barriers and facilitators were mapped to behaviour change techniques, focussing on the intervention types of education, persuasion and environmental restructuring, alongside appropriate modes of delivery, and prototype intervention materials were developed. (iii) We iteratively refined these materials in a workshop with multidisciplinary experts and Patient and Public Involvement and Engagement (PPIE) representatives (n = 13) and an (iv) intervention walkthrough with families (n = 5). The design process was informed by the Behaviour Change Wheel, Theoretical framework of acceptability and the Template for intervention description and replication. RESULTS: Social influences and motivational factors are likely to influence both uptake and adherence to the intervention. Anticipated emotional reward from participating in research for the benefit of others was indicated to be a strong facilitator for intervention uptake. Alternatives to bathing, having fun with the baby and the night-time routine, alongside family support, were notable facilitators suggested to aid adherence to the intervention. Barriers included hygiene concerns and anticipated negative social appraisal. Barriers and facilitators were mapped to thirty-six behaviour change techniques, focussing on the intervention types of education, persuasion and environmental restructuring, all of which were embedded into the package of support. The prototype intervention materials received positive feedback from the expert workshop and study walkthrough with families. The final package of support comprises printed and digital prompts and cues, a study booklet, video, and digital tool for self-monitoring. CONCLUSIONS: The intervention design process incorporated the 'real world' views and experiences of families, experts and PPIE representatives, alongside criteria for designing behavioural interventions. The effectiveness of the package of support will be tested in a feasibility trial and embedded process evaluation.

Interferon-ß deficiency alters brain response to chronic HIV-1 envelope protein exposure in a transgenic model of NeuroHIV.

Human immunodeficiency virus-1 (HIV-1) infects the central nervous system (CNS) and causes HIV-associated neurocognitive disorders (HAND) in about half of the population living with the virus despite combination anti-retroviral therapy (cART). HIV-1 activates the innate immune system, including the production of type 1 interferons (IFNs) α and ß. Transgenic mice expressing HIV-1 envelope glycoprotein gp120 (HIVgp120tg) in the CNS develop memory impairment and share key neuropathological features and differential CNS gene expression with HIV patients, including the induction of IFN-stimulated genes (ISG). Here we show that knocking out IFNß (IFNßKO) in HIVgp120tg and non-tg control mice impairs recognition and spatial memory, but does not affect anxiety-like behavior, locomotion, or vision. The neuropathology of HIVgp120tg mice is only moderately affected by the KO of IFNß but in a sex-dependent fashion. Notably, in cerebral cortex of IFNßKO animals presynaptic terminals are reduced in males while neuronal dendrites are reduced in females. The IFNßKO results in the hippocampal CA1 region of both male and female HIVgp120tg mice in an ameliorated loss of neuronal presynaptic terminals but no protection of neuronal dendrites. Only female IFNß-deficient HIVgp120tg mice display diminished microglial activation in cortex and hippocampus and increased astrocytosis in hippocampus compared to their IFNß-expressing counterparts. RNA expression for some immune genes and ISGs is also affected in a sex-dependent way. The IFNßKO abrogates or diminishes the induction of MX1, DDX58, IRF7 and IRF9 in HIVgp120tg brains of both sexes. Expression analysis of neurotransmission related genes reveals an influence of IFNß on multiple components with more pronounced changes in IFNßKO females. In contrast, the effects of IFNßKO on MAPK activities are independent of sex with pronounced reduction of active ERK1/2 but also of active p38 in the HIVgp120tg brain. In summary, our findings show that the absence of IFNß impairs memory dependent behavior and modulates neuropathology in HIVgp120tg brains, indicating that its absence may facilitate development of HAND. Moreover, our data suggests that endogenous IFNß plays a vital role in maintaining neuronal homeostasis and memory function.

A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury.

Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive. Here we show that cysteinyl-leukotrienes (CysLT) released by HIV-infected or HIVgp120 stimulated MΦ downstream of p38 MAPK critically contribute to neurotoxicity. SiRNA-mediated or pharmacological inhibition of p38 MAPK deprives MΦ of CysLT synthase (LTC4S) and, pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CYSLTR1) protects cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected MΦ. Components of the CysLT pathway are differentially regulated in brains of HIV-infected individuals and a transgenic mouse model of NeuroHIV (HIVgp120tg). Moreover, genetic ablation of LTC4S or CysLTR1 prevents neuronal damage and impairment of spatial memory in HIVgp120tg mice. Altogether, our findings suggest a novel critical role for cysteinyl-leukotrienes in HIV-associated brain injury.

Cost-effectiveness of two online interventions supporting self-care for eczema for parents/carers and young people.

OBJECTIVE: To estimate the cost-effectiveness of online behavioral interventions (EczemaCareOnline.org.uk) designed to support eczema self-care management for parents/carers and young people from an NHS perspective. METHODS: Two within-trial economic evaluations, using regression-based approaches, adjusting for baseline and pre-specified confounder variables, were undertaken alongside two independent, pragmatic, parallel group, unmasked randomized controlled trials, recruiting through primary care. Trial 1 recruited 340 parents/carers of children aged 0-12 years and Trial 2 337 young people aged 13-25 years with eczema scored ≥ 5 on Patient-Oriented Eczema Measure (POEM). Participants were randomized (1:1) to online intervention plus usual care or usual care alone. Resource use, collected via medical notes review, was valued using published unit costs in UK £Sterling 2021. Quality-of-life was elicited using proxy CHU-9D in Trial 1 and self-report EQ-5D-5L in Trial 2. RESULTS: The intervention was dominant (cost saving and more effective) with a high probability of cost-effectiveness (> 68%) in most analyses. The exception was the complete case cost-utility analysis for Trial 1 (omitting participants with children aged < 2), with adjusted incremental cost savings of -£34.15 (95% CI - 104.54 to 36.24) and incremental QALYs of - 0.003 (95% CI - 0.021 to 0.015) producing an incremental cost per QALY of £12,466. In the secondary combined (Trials 1 and 2) cost-effectiveness analysis, the adjusted incremental cost was -£20.35 (95% CI - 55.41 to 14.70) with incremental success (≥ 2-point change on POEM) of 10.3% (95% CI 2.3-18.1%). CONCLUSION: The free at point of use online eczema self-management intervention was low cost to run and cost-effective. TRIAL REGISTRATION: This trial was registered prospectively with the ISRCTN registry (ISRCTN79282252). URL www.EczemaCareOnline.org.uk .

A Two-Phase Qualitative Enquiry Into Storytelling's Potential to Support Palliative Care Patient-Led Change, Using a Systematic Review Approach.

A terminal diagnosis can diminish an individual's sense of agency and identity. Leading change appears to restore a sense of agential self. The first phase of this literature review explores factors influencing patient-led change across the palliative care ecosystem. The second phase illuminates how storytelling can support palliative care patients in leading ecosystem-wide change. 35 studies were identified in Phase 1 and 36 in Phase 2. This research highlights the need to situate patient leadership activity within a palliative care ecosystem to understand factors likely to support or hinder patient leadership activity within it. The evidence indicates the potential use of storytelling to support patients with a life-limiting illness to lead change across the palliative care ecosystem. This challenges current conceptualisations of such patients and offers them instead as an additional source of palliative care support.

A reverse translational study of PPAR-α agonist efficacy in human and rodent models relevant to alcohol use disorder.

Alcohol Use Disorder (AUD) is a chronic relapsing disorder affecting an estimated 283 million individuals worldwide, with substantial health and economic consequences. Peroxisome proliferator-activated receptors (PPARs), particularly PPAR-α and PPAR-γ, have shown promise in preclinical studies as potential therapeutic targets for AUD. In this human laboratory study, we aimed to translate preclinical findings on the PPAR-α agonist fenofibrate to a human population with current AUD. We hypothesized that, relative to placebo, fenofibrate at the highest FDA-approved dose of 145 mg/d would attenuate responsiveness to in vivo alcohol cues in the lab and reduce drinking under natural conditions. However, the results did not show significant differences in craving and alcohol consumption between the fenofibrate and placebo groups. Reverse translational studies in rodent models confirmed the lack of fenofibrate effect at human-equivalent doses. These findings suggest that inadequate translation of drug dose from rodents to humans may account for the lack of fenofibrate effects on alcohol craving and consumption in humans with AUD. The results highlight the need for new brain-penetrant PPAR-α agonists to adequately test the therapeutic potential of PPAR-α agonists for AUD, and the importance of reverse translational approaches and selection of human-equivalent doses in drug development.

Virtual reality used to distract children and young people with long-term conditions from pain or pruritus: A scoping review using PAGER.

AIMS AND OBJECTIVES: To map out the primary research studies relating to how virtual reality (VR) has been used to distract children and young people with long-term conditions from pain or pruritus. BACKGROUND: Pharmacologic treatment of chronic pain and pruritus may have side effects; hence, non-invasive non-pharmacological treatments are being sought. DESIGN: The scoping review followed the methodology recommended by the Joanna Briggs Institute, PAGER framework and PRISMA-ScR checklist. The protocol was registered with the Open Science Registration on 14 February 2022 https//doi.org/10.17605/OSF.IO/K2R93. METHODS: Five databases (Medline, CINAHL, PsycINFO, Web of Science and Scopus) were searched. Data were extracted from primary research studies published between 2000 and 2022 involving children and adolescent populations (<21 years) with a long-term condition that had an element of enduring pruritus and/or pain. RESULTS: Of 464 abstracts screened, 35 full-text papers were assessed with 5 studies meeting the eligibility criteria. Three main themes emerged from the included studies: (1) Improvements in pain and daily functioning; (2) positive perceptions of VR and (3) accessibility and feasibility of VR. No papers were found on the effect of VR on alleviating pruritus. CONCLUSION: VR is feasible, acceptable, and safe for children and adolescents with chronic pain in a range of long-term conditions and offers promise as an adjunctive treatment for improving chronic pain and quality of life. No studies were identified that targeted pruritis or measured pruritis outcomes; thus, the effects of VR for pruritis are unknown. There is a need for rigorously designed, randomised controlled trials to test the clinical and cost-effectiveness of VR interventions for chronic pain and pruritis in children and adolescents. The use of the PAGER (Patterns, Advances, Gaps, Evidence for Practice and Research Recommendations) framework for scoping reviews helped to structure analysis and findings and identify research gaps. RELEVANCE TO CLINICAL PRACTICE: VR interventions offer promise in improving chronic pain related to long-term conditions.

Cell-type brain-region specific changes in prefrontal cortex of a mouse model of alcohol dependence.

The prefrontal cortex is a crucial regulator of alcohol drinking, and dependence, and other behavioral phenotypes associated with AUD. Comprehensive identification of cell-type specific transcriptomic changes in alcohol dependence will improve our understanding of mechanisms underlying the excessive alcohol use associated with alcohol dependence and will refine targets for therapeutic development. We performed single nucleus RNA sequencing (snRNA-seq) and Visium spatial gene expression profiling on the medial prefrontal cortex (mPFC) obtained from C57BL/6 J mice exposed to the two-bottle choice-chronic intermittent ethanol (CIE) vapor exposure (2BC-CIE, defined as dependent group) paradigm which models phenotypes of alcohol dependence including escalation of alcohol drinking. Gene co-expression network analysis and differential expression analysis identified highly dysregulated co-expression networks in multiple cell types. Dysregulated modules and their hub genes suggest novel understudied targets for studying molecular mechanisms contributing to the alcohol dependence state. A subtype of inhibitory neurons was the most alcohol-sensitive cell type and contained a downregulated gene co-expression module; the hub gene for this module is Cpa6, a gene previously identified by GWAS to be associated with excessive alcohol consumption. We identified an astrocytic Gpc5 module significantly upregulated in the alcohol-dependent group. To our knowledge, there are no studies linking Cpa6 and Gpc5 to the alcohol-dependent phenotype. We also identified neuroinflammation related gene expression changes in multiple cell types, specifically enriched in microglia, further implicating neuroinflammation in the escalation of alcohol drinking. Here, we present a comprehensive atlas of cell-type specific alcohol dependence mediated gene expression changes in the mPFC and identify novel cell type-specific targets implicated in alcohol dependence.

Ethanol's interaction with BK channel α subunit residue K361 does not mediate behavioral responses to alcohol in mice.

Large conductance potassium (BK) channels are among the most sensitive molecular targets of ethanol and genetic variations in the channel-forming α subunit have been nominally associated with alcohol use disorders. However, whether the action of ethanol at BK α influences the motivation to drink alcohol remains to be determined. To address this question, we first tested the effect of systemically administered BK channel modulators on voluntary alcohol consumption in C57BL/6J males. Penitrem A (blocker) exerted dose-dependent effects on moderate alcohol intake, while paxilline (blocker) and BMS-204352 (opener) were ineffective. Because pharmacological manipulations are inherently limited by non-specific effects, we then sought to investigate the behavioral relevance of ethanol's direct interaction with BK α by introducing in the mouse genome a point mutation known to render BK channels insensitive to ethanol while preserving their physiological function. The BK α K361N substitution prevented ethanol from reducing spike threshold in medial habenula neurons. However, it did not alter acute responses to ethanol in vivo, including ataxia, sedation, hypothermia, analgesia, and conditioned place preference. Furthermore, the mutation did not have reproducible effects on alcohol consumption in limited, continuous, or intermittent access home cage two-bottle choice paradigms conducted in both males and females. Notably, in contrast to previous observations made in mice missing BK channel auxiliary ß subunits, the BK α K361N substitution had no significant impact on ethanol intake escalation induced by chronic intermittent alcohol vapor inhalation. It also did not affect the metabolic and locomotor consequences of chronic alcohol exposure. Altogether, these data suggest that the direct interaction of ethanol with BK α does not mediate the alcohol-related phenotypes examined here in mice.