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The cell adhesion molecule leucine-rich repeat transmembrane neuronal protein 2 (LRRTM2) is crucial for synapse development and function. However, our understanding of its endogenous trafficking has been limited due to difficulties in manipulating its coding sequence (CDS) using standard genome editing techniques. Instead, we replaced the entire LRRTM2 CDS by adapting a two-guide CRISPR knock-in method, enabling complete control of LRRTM2. In primary rat hippocampal cultures dissociated from embryos of both sexes, N-terminally tagged, endogenous LRRTM2 was found in 80% of synapses, and synaptic LRRTM2 content correlated with PSD-95 and AMPAR levels. LRRTM2 was also enriched with AMPARs outside synapses, demonstrating the sensitivity of this method to detect relevant new biology. Finally, we leveraged total genomic control to increase the synaptic levels of LRRTM2 via simultaneous mutation of its C-terminal domain, which did not correspondingly increase AMPAR enrichment. The coding region of thousands of genes span lengths suitable for whole-CDS replacement, suggesting this simple approach will enable straightforward structure–function analysis in neurons. [ABSTRACT FROM AUTHOR]

Sleep disturbances are associated with intrusive memories, but the neurocognitive mechanisms underpinning this relationship are poorly understood. Here, we show that sleep deprivation disrupts prefrontal inhibition of memory retrieval, and that the overnight restoration of this inhibitory mechanism is associated with time spent in rapid eye movement (REM) sleep. The functional impairments arising from sleep deprivation are linked to a behavioral deficit in the ability to downregulate unwanted memories, and coincide with a deterioration of deliberate patterns of self-generated thought. We conclude that sleep deprivation gives rise to intrusive memories via the disruption of neural circuits governing mnemonic inhibitory control, which may rely on REM sleep. [ABSTRACT FROM AUTHOR]

Objective To map how social, commercial, political and digital determinants of health have changed or emerged during the recent digital transformation of society and to identify priority areas for policy action. Methods We systematically searched MEDLINE, Embase and Web of Science on 24 September 2023, to identify eligible reviews published in 2018 and later. To ensure we included the most recent literature, we supplemented our review with non-systematic searches in PubMed® and Google Scholar, along with records identified by subject matter experts. Using thematic analysis, we clustered the extracted data into five societal domains affected by digitalization. The clustering also informed a novel framework, which the authors and contributors reviewed for comprehensiveness and accuracy. Using a two-round consensus process, we rated the identified determinants into high, moderate and low urgency for policy actions. Findings We identified 13 804 records, of which 204 met the inclusion criteria. A total of 127 health determinants were found to have emerged or changed during the digital transformation of society (37 digital, 33 social, 33 commercial and economic and 24 political determinants). Of these, 30 determinants (23.6%) were considered particularly urgent for policy action. Conclusion This review offers a comprehensive overview of health determinants across digital, social, commercial and economic, and political domains, highlighting how policy decisions, individual behaviours and broader factors influence health by digitalization. The findings deepen our understanding of how health outcomes manifest within a digital ecosystem and inform strategies for addressing the complex and evolving networks of health determinants. [ABSTRACT FROM AUTHOR]

Background: Over the past decade, the number of clinical pharmacists working within multidisciplinary teams in English general practices has expanded., Aim: To examine changes in quality of prescribing after the adoption of clinical pharmacist roles in English general practices., Design and Setting: Longitudinal cohort study in English general practice., Method: Two-way fixed-effects regression was used to compare differences in prescribing indicators in general practices with and without pharmacists between September 2015 and December 2019., Results: Between September 2015 and December 2019, the proportion of practices employing a clinical pharmacist increased from 236/7623 (3.1%) to 1402/6836 (20.5%). Clinical pharmacist implementation resulted in statistically significant reductions in total costs of medicines per 1000 patients (-0.85%, 95% confidence interval [CI] = -1.50% to -0.21%), the total number of opioid prescriptions per 1000 patients (-1.06%, 95% CI = -1.82% to -0.29%), and the average daily quantity of anxiolytics per 1000 patients (-1.26%, 95% CI = -2.40% to -0.12%). Clinical pharmacist implementation also resulted in reductions in the total number of prescriptions per 1000 patients (-0.58%, 95% CI = -1.30% to 0.13%) and the total number of antibiotic prescriptions per 1000 patients (-0.51%, 95% CI = -1.30% to 0.27%) that trended towards statistical significance. There were no statistically significant differences in the share of broad-spectrum versus narrow-spectrum antibiotics (0.02%, 95% CI = -0.07% to 0.11%) and the oral morphine equivalence of high-dose opioids (>120 mg per 24 h) per 1000 patients (1.19%, 95% CI = -0.46% to 2.85%)., Conclusion: This analysis is limited by practice-level data but supports the hypothesis that clinical pharmacist implementation results in improvements in prescribing quality., (© The Authors.)

Background and Aims: Direct (medical and non-medical) and indirect (production losses and informal care) costs of cardiovascular disease (CVD) have been captured in two previous United Kingdom (UK) cost-of-illness studies, but the areas of long-term care and medical device costs were neglected. We aimed to quantify the economic burden of CVD in the UK from a societal perspective between fiscal years 2019/20 to 2021/22., Methods: Mixed-methods study in a prevalence-based retrospective review of economic costs focused on the public sector. Top-down costing was applied to the following areas: inpatient hospital care, outpatient specialist care, emergency care, primary care, medications, medical devices, long-term care, production losses to morbidity, and production losses to mortality. Bottom-up costing was used by applying the marginal effects of having a cardiovascular disease on several parameters using survey data from the Survey on Health, Aging, and Retirement in Europe to estimate informal care costs., Results: The modelling performed shows that the total costs of CVD in the UK in 2021/22 were £29.021 billion (bn), with direct costs of £16.620 bn and indirect costs of £12.402 bn. The breakdown of direct costs for the UK were inpatient care (£6.732 bn), long-term care (£4.649 bn), medications (£1.940 bn), primary care (£1.556 bn), outpatient care (£1.011 bn), emergency care (£327.6 million (mn)), and medical devices (£404.4 mn). The breakdown of indirect costs for the UK were informal care costs (£6.377 bn), production losses to mortality (£4.544 bn), and production losses to morbidity (£1.481 bn)., Conclusion: There is a significant economic burden of CVD in the UK, with the highest direct cost resulting from inpatient care and the highest indirect cost resulting from informal care., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Antimicrobial resistance (AMR) is one of the biggest public health challenges of our time. National Action Plans have failed so far to effectively address socioeconomic drivers of AMR, including the animal and environmental health dimensions of One Health., Objective: To map what socioeconomic drivers of AMR exist in the literature with quantitative evidence., Methods: An umbrella review was undertaken across Medline, Embase, Global Health, and Cochrane Database of Systematic Reviews, supplemented by a grey literature search on Google Scholar. Review articles demonstrating a methodological search strategy for socioeconomic drivers of AMR were included. Two authors extracted drivers from each review article which were supported by quantitative evidence. Drivers were grouped thematically and summarised narratively across the following three layers of society: People & Public, System & Environment, and Institutions & Policies., Results: The search yielded 6300 articles after deduplication, with 23 review articles included. 27 individual thematic groups of drivers were identified. The People & Public dimensions contained the following themes: age, sex, ethnicity, migrant status, marginalisation, sexual behaviours, socioeconomic status, educational attainment, household composition, maternity, personal hygiene, lifestyle behaviours. System & Environment yielded the following themes: household transmission, healthcare occupation, urbanicity, day-care attendance, environmental hygiene, regional poverty, tourism, animal husbandry, food supply chain, water contamination, and climate. Institutions & Policies encompassed poor antibiotic quality, healthcare financing, healthcare governance, and national income. Many of these contained bidirectional quantitative evidence, hinting at conflicting pathways by which socioeconomic factors drive AMR., Conclusion: This umbrella review maps socioeconomic drivers of AMR with quantitative evidence, providing a macroscopic view of the complex pathways driving AMR. This will help direct future research and action on socioeconomic drivers of AMR., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Elias Mossialos reports financial support was provided by World Economic Forum. Victoria Saint reports a relationship with World Health Organization that includes: consulting or advisory. Victoria Saint reports a relationship with German Alliance for Global Health Research that includes: funding grants. Victoria Saint reports a relationship with ERASMUS Programme that includes: travel reimbursement. Alison Shutt reports a relationship with National Institute for Health Research that includes: funding grants. Esmita Charani reports a relationship with Pfizer that includes: speaking and lecture fees. Esmita Charani reports a relationship with bioMérieux Inc. that includes: speaking and lecture fees. Esmita Charani reports a relationship with World Health Organization that includes: funding grants. Esmita Charani reports a relationship with Wellcome Trust that includes: funding grants. Michael Anderson reports a relationship with World Health Organization Regional Office for Europe that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025 The Authors.)

Tight coordination of the spatial relationships between protein complexes is required for cellular function. In neuronal synapses, many proteins responsible for neurotransmission organize into subsynaptic nanoclusters whose trans-cellular alignment modulates synaptic signal propagation. However, the spatial relationships between these proteins and NMDA receptors (NMDARs), which are required for learning and memory, remain undefined. Here, we mapped the relationship of key NMDAR subunits to reference proteins in the active zone and postsynaptic density using multiplexed super-resolution DNA-PAINT microscopy. GluN2A and GluN2B subunits formed nanoclusters with diverse configurations that, surprisingly, were not localized near presynaptic vesicle release sites marked by Munc13-1. Despite this, we found a subset of release sites was enriched with NMDARs, and modeling of glutamate release and receptor activation in measured synapses indicated this nanotopography promotes NMDAR activation. This subset of release sites was internally denser with Munc13-1, aligned with abundant PSD-95, and associated closely with specific NMDAR nanodomains. Further, NMDAR activation drove rapid reorganization of this release site/receptor relationship, suggesting a structural mechanism for tuning NMDAR-mediated synaptic transmission. This work reveals a new principle regulating NMDAR signaling and suggests that synaptic functional architecture depends on the assembly of and trans-cellular spatial relationships between multiprotein nanodomains., Competing Interests: Competing interests: All authors declare no competing interests.

Background: The mechanisms underlying generalized forms of dissociative ('psychogenic') amnesia are poorly understood. One theory suggests that memory retrieval is inhibited via prefrontal control. Findings from cognitive neuroscience offer a candidate mechanism for this proposed retrieval inhibition. By applying predictions based on these experimental findings, we examined the putative role of retrieval suppression in dissociative amnesia., Methods: We analyzed fMRI data from two previously reported cases of dissociative amnesia. Patients had been shown reminders from forgotten and remembered time periods (colleagues and school friends). We examined the neuroanatomical overlap between regions engaged in the unrecognized compared to the recognized condition, and the regions engaged during retrieval suppression in laboratory-based tasks. Effective connectivity analyses were performed to test the hypothesized modulatory relationship between the right anterior dorsolateral prefrontal cortex (raDLPFC) and the hippocampus. Both patients were scanned again following treatment, and analyses were repeated., Results: We observed substantial functional alignment between the inhibitory regions engaged during laboratory-based retrieval suppression tasks, and those engaged when patients failed to recognize their current colleagues. This included significant activation in the raDLPFC and right ventrolateral prefrontal cortex, and a corresponding deactivation across autobiographical memory regions (hippocampus, medial PFC). Dynamic causal modeling confirmed the hypothesized modulatory relationship between the raDLPFC and the hippocampus. This pattern was no longer evident following memory recovery in the first patient, but persisted in the second patient who remained amnesic., Conclusions: Findings are consistent with an inhibitory mechanism driving down activity across core memory regions to prevent the recognition of personally relevant stimuli.