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Origin and evolution of bacterial periplasmic force transducers.

In double-membraned bacteria, non-equilibrium processes that occur at the outer membrane (OM) are typically coupled to the chemiosmotically-energised inner membrane (IM). TolA and TonB are homologous proteins which energetically couple IM motor proteins to the essential processes of OM-stabilisation and substrate import, respectively. The evolutionary trajectories of these proteins have been difficult to elucidate due to low sequence conservation, yet they are thought to transduce force similarly. Here, this problem was addressed using structural prediction approaches to identify and annotate force transduction operons to trace their distribution and evolutionary origins. In the process, we identify a novel OM-tethering system and a previously unknown family of monomeric force transducers. This approach revealed putative tolA genes, and thus the core organisational principles of the tol-pal operon throughout diverse bacterial taxa. We discovered that the α-helical structure of the periplasm-spanning domain II of TolA previously thought its hallmark, is anomalous amongst most Tol-Pal systems. This structure is mainly prevalent in γ-proteobacteria, likely in adaptation to their lifestyle. Comparison of Tol-Pal and Ton system distribution suggests that TolA emerged from a TonB paralogue and co-emerged with Pal, the OM-tethering lipoprotein that functionalises the Tol-Pal system. We also determined that TolB, the Pal-mobilising protein, likely emerged from a family of outer membrane proteins (OMPs); and CpoB, a periplasmic factor that coordinates peptidoglycan remodelling with cell division, was originally a lipoprotein present in the ancestral Tol-Pal system. The extensive conservation of the Tol-Pal system throughout Gracilicutes highlights its significance in bacterial cell biology.

Humans adapt rationally to approximate estimates of uncertainty.

Differential Associations of Dopamine and Serotonin With Reward and Punishment Processes in Humans: A Systematic Review and Meta-Analysis.

IMPORTANCE: Mechanistic biomarkers for guiding treatment selection require selective sensitivity to specific pharmacological interventions. Reinforcement learning processes show potential, but there have been conflicting and sometimes inconsistent reports on how dopamine and serotonin-2 key targets in treating common mental illnesses-affect reinforcement learning in humans. OBJECTIVE: To perform a meta-analysis of pharmacological manipulations of dopamine and serotonin and examine whether they show distinct associations with reinforcement learning components in humans. DATA SOURCES: Ovid MEDLINE/PubMed, Embase, and PsycInfo databases were searched for studies published between January 1, 1946, and January 19, 2023 (repeated April 9, 2024, and October 15, 2024), investigating dopaminergic or serotonergic effects on reward and punishment processes in humans according to PRISMA guidelines. STUDY SELECTION: Studies reporting randomized, placebo-controlled, dopaminergic or serotonergic manipulations on a behavioral outcome from a reward or punishment processing task in healthy humans were included. DATA EXTRACTION AND SYNTHESIS: Standardized mean difference (SMD) scores were calculated for the comparison between each drug (dopamine or serotonin) and placebo on a behavioral reward or punishment outcome and quantified in random-effects models for overall reward or punishment processes and 4 main subcategories. Study quality (Cochrane Collaboration tool), moderators, heterogeneity, and publication bias were also assessed. MAIN OUTCOMES AND MEASURES: Performance on reward or punishment processing tasks. RESULTS: In total, 102 studies conducted among healthy volunteers were included (2291 participants receiving dopamine vs 2284 receiving placebo and 1491 receiving serotonin vs 1523 receiving placebo). Dopamine was associated with an increase in overall reward (SMD, 0.18; 95% CI, 0.09 to 0.28) but not punishment function (SMD, -0.06; 95% CI, -0.26 to 0.13). Serotonin was not meaningfully associated with overall punishment (SMD, 0.22; 95% CI, -0.04 to 0.49) or reward (SMD, 0.02; 95% CI, -0.33 to 0.36). Dopaminergic and serotonergic manipulations had distinct associations with subcomponents. Dopamine was associated with reward learning or sensitivity (SMD, 0.26; 95% CI, 0.11 to 0.40), reward discounting (SMD, -0.08; 95% CI, -0.14 to -0.01), and reward vigor (SMD, 0.32; 95% CI, 0.11 to 0.54). By contrast, serotonin was associated with punishment learning or sensitivity (SMD, 0.32; 95% CI, 0.05 to 0.59), reward discounting (SMD, -0.35; 95% CI, -0.67 to -0.02), and aversive pavlovian processes (within-participant studies only; SMD, 0.36; 95% CI, 0.20 to 0.53). CONCLUSIONS AND RELEVANCE: In this study, pharmacological manipulations of both dopamine and serotonin had measurable associations with reinforcement learning in humans. The selective associations with different components suggest that reinforcement learning tasks could form the basis of selective, mechanistically interpretable biomarkers to support treatment assignment.

Latent Profiles of Early Language Development in a Large Finnish-Speaking Sample of the FinnBrain Birth Cohort Study.

PURPOSE: Research on early language development has primarily used two categories to group at-risk children, differing by the age at which risk is identified. Late talkers are toddlers with late onset of language development, some of whom may catch up with peers. Developmental language disorder is used to refer to children above the age of 4 years. To this day, the longitudinal relationship between the two categories remains unclear. In this study, we explored early language trajectories in a large birth cohort using exploratory methodology to gain better understanding of the types and prevalence of language trajectories from 14 months to 5 years of age, with particular interest in risk trajectories that cluster statistically. METHOD: We conducted latent profile analysis (LPA) on seven language variables collected between 1 and 5 years of age (N = 1,281). Multinomial logistic regression procedure was used to identify child and family characteristics that predicted profile memberships. RESULTS: The LPA yielded three profiles of language development described as persistent low, stable average, and stable high. Female sex, longer duration of pregnancy, and higher maternal socioeconomic status increased the odds of belonging to the stable high-language profile, whereas male sex and not being first born increased the odds of belonging to persistent low language profile. CONCLUSIONS: Contrary to previous research, we did not observe increasing or decreasing profiles, suggesting that toddler language difficulties tend to persist at age 5 years, at least in this birth cohort. This suggests commencing language intervention early instead of the wait-and-see approach. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.29441471.

Building capacity in the academic general practice research workforce.

Implementing Acute Stroke Services in Sub-Saharan Africa: Steps, Progress, and Perspectives from the Tanzania Stroke Project.

INTRODUCTION: Stroke is a leading cause of morbidity and mortality globally, with Africa bearing a disproportionately high burden of poor outcomes. In sub-Saharan Africa, acute stroke care remains inconsistent, with organized stroke units being either absent or rarely available, contributing to the high stroke mortality rates in the region. To address this issue, the Tanzania Stroke Project (TSP) was launched, aimed at establishing acute stroke services at two of the largest tertiary care centers in collaboration with the Tanzanian Ministry of Health, the World Stroke Organization, and Hospital Directorates. METHODS: TSP utilized a three-tier implementation approach to establish a more organized stroke care system in two large academic hospitals. Here, we detail the process of this initiative, which took place between August 2023 and August 2024. The three-tier approach included (1) the establishment of stroke registries; (2) the training of healthcare workers (HCWs); and (3) the development of acute stroke protocols and establishment of stroke units at Muhimbili National Hospital-Mloganzila and Bugando Medical Center in Tanzania. RESULTS: In tier one (stroke registry), two comprehensive stroke registries were established, including 460 adults (mean age 60 ± 15 years). Hemorrhagic stroke was the most common subtype, accounting for 59% of cases (n = 269). Premorbid hypertension was the most prevalent risk factor, affecting 81% (n = 373) of the patients. More than half of patients (58%, n = 171) arrived at the hospital after 24 h from stroke symptoms. Only 11% (n = 50/452) had documented swallowing screenings, and among patients with intracerebral hemorrhage, 11% (n = 28/251) achieved the target for blood pressure control, while 47% (n = 99/213) met blood glucose control targets. The in-hospital mortality rate was 27% (n = 93/340). In tier two (training of HCWs), extensive evidence-based mentorship training was provided with higher participation rates among HCWs at Bugando Medical Center compared to Muhimbili National Hospital-Mloganzila (57% [29/51] vs. 23% [7/31], p = 0.002). In tier three (stroke unit protocols), stroke protocols were developed based on the training and current evidence, leading to the establishment of dedicated stroke units at each facility, with a minimum of 8 beds per unit. The full impact of these implementations has yet to be fully assessed. CONCLUSION: This was the first initiative to implement stroke services at two large tertiary healthcare centers in Tanzania. Our findings highlight the importance of multilevel stakeholder engagement through a 3-tier approach in countries starting to establish stroke services and the need for ongoing quality-of-care monitoring and continuous efforts to sensitize both HCWs and the broader community.

Evolution and significance of neuronal surface autoantibodies after Japanese encephalitis.

NMDAR-antibody encephalitis can arise as a post-infectious 'relapse' following HSV encephalitis. We asked whether a similar condition might occur after Japanese Encephalitis (JE). Cell-based assays for antigen-specific antibodies and IgG binding to the surface of live hippocampal neurons were performed on 13 CSFs and 65 sera, many sampled longitudinally, from 34 Vietnamese children with JE. Three month outcomes were scored according to a pediatric post-encephalitis scale; clinical features focussed on new onset symptoms during the follow-up, blinded to antibody results. Ten/34 children (29 %) had serum antibodies against known neuronal-surface antigens, 4 NMDAR, 4 CASPR2, 1 GABAAR and 1 LGI1, detected from day 23 after onset. In addition, 8/10 (80 %) of these children and 13/24 (54 %) others had antibodies that bound in a distinctive pattern to live hippocampal neurons (HN-Abs), four detected on days 9-12. A relapse was only considered possible in 5 patients, two with specific neuronal surface antibodies (NSAbs). Neither specific NSAbs (p = 1.00) nor HN-Abs (p = 1.00).were more common in patients with possible relapse than in those with unlikely relapse. There was a modest trend towards worse outcome scores in patients with known NSAbs than in the remaining patients (p = 0.089). Antibodies to neuronal surface proteins, known and unknown, are common in children after JE. Caution is urged in defining post-infectious autoimmune encephalitis on the basis of a positive neuronal antibody and new onset symptoms or deterioration following recovery from JE, or in initiating immunotherapy without confirmatory evidence of a time-dependent encephalitic illness defined by published guidelines.

Language and beyond: a registered report examining single and multiple risk models of later reading comprehension weaknesses

Clinical Prediction Models Incorporating Blood Test Trend for Cancer Detection: Systematic Review, Meta-Analysis, and Critical Appraisal.

BACKGROUND: Blood tests used to identify patients at increased risk of undiagnosed cancer are commonly used in isolation, primarily by monitoring whether results fall outside the normal range. Some prediction models incorporate changes over repeated blood tests (or trends) to improve individualized cancer risk identification, as relevant trends may be confined within the normal range. OBJECTIVE: Our aim was to critically appraise existing diagnostic prediction models incorporating blood test trends for the risk of cancer. METHODS: MEDLINE and EMBASE were searched until April 3, 2025 for diagnostic prediction model studies using blood test trends for cancer risk. Screening was performed by 4 reviewers. Data extraction for each article was performed by 2 reviewers independently. To critically appraise models, we narratively synthesized studies, including model building and validation strategies, model reporting, and the added value of blood test trends. We also reviewed the performance measures of each model, including discrimination and calibration. We performed a random-effects meta-analysis of the c-statistic for a trends-based prediction model if there were at least 3 studies validating the model. The risk of bias was assessed using the PROBAST (prediction model risk of bias assessment tool). RESULTS: We included 16 articles, with a total of 7 models developed and 14 external validation studies. In the 7 models derived, full blood count (FBC) trends were most commonly used (86%, n=7 models). Cancers modeled were colorectal (43%, n=3), gastro-intestinal (29%, n=2), nonsmall cell lung (14%, n=1), and pancreatic (14%, n=1). In total, 2 models used statistical logistic regression, 2 used joint modeling, and 1 each used XGBoost, decision trees, and random forests. The number of blood test trends included in the models ranged from 1 to 26. A total of 2 of 4 models were reported with the full set of coefficients needed to predict risk, with the remaining excluding at least one coefficient from their article or were not publicly accessible. The c-statistic ranged 0.69-0.87 among validation studies. The ColonFlag model using trends in the FBC was commonly externally validated, with a pooled c-statistic=0.81 (95% CI 0.77-0.85; n=4 studies) for 6-month colorectal cancer risk. Models were often inadequately tested, with only one external validation study assessing model calibration. All 16 studies scored a low risk of bias regarding predictor and outcome details. All but one study scored a high risk of bias in the analysis domain, with most studies often removing patients with missing data from analysis or not adjusting the derived model for overfitting. CONCLUSIONS: Our review highlights that blood test trends may inform further investigation for cancer. However, models were not available for most cancer sites, were rarely externally validated, and rarely assessed calibration when they were externally validated.

The cognitive neuroscience of ketamine in major depression.

Ketamine's potential as a rapid-acting antidepressant was first identified in 2000, despite its long-standing use as an anesthetic agent. Clinically, ketamine alleviates depressive symptoms, including the difficult to treat symptom of anhedonia, within hours, with the effects of a single dose lasting for days. Since then, research has focused on uncovering the mechanisms underlying its rapid antidepressant effects in both humans and animal models. While its molecular and cellular effects have been extensively characterized, its impact on cognitive and neuropsychological mechanisms - potential mediators of its clinical efficacy - remains an area of ongoing investigation. Preclinical studies suggest that ketamine rapidly influences the lateral habenula (involved in punishment processing) and fronto-striatal (reward) systems, reverses negative affective biases in established memories, and promotes long-term stress resilience. Translating these findings to human models is crucial, and emerging evidence suggests that ketamine engages similar mechanisms in healthy volunteer and patient groups. However, its clinical application is constrained by acute side effects and an unknown long-term safety profile. Further research into ketamine's mechanisms of action will be essential to inform the development of novel, safer, and more accessible rapid-acting antidepressants.

FMR1 KH0-KH1 domains coordinate m6A binding and phase separation in Fragile X syndrome.

Fragile X messenger ribonucleoprotein 1 (FMR1) regulates neurodevelopment through m6A RNA interactions, yet the domain-specific roles of KH0 and KH1 in RNA binding and disease pathogenesis remain poorly understood. Using mutagenesis and AlphaFold3 structural modeling, we identify KH1 as the primary m6A-binding interface, while the KH0 domain (particularly Arg138) modulates liquid-liquid phase separation (LLPS). Pathogenic mutations in KH0 impair RNA binding and promote aberrant LLPS aggregation, whereas m6A-modified RNA suppresses LLPS formation at KH0. Structural simulations uncover synergistic interactions between KH0 and KH1 mediated by hydrophobic and electrostatic networks. These domain-specific cooperations establish a mechanistic link between m6A dysregulation, pathological phase separation, and Fragile X syndrome pathogenesis. Our findings nominate KH0 as a potential therapeutic target for RNA-driven neurodevelopmental disorders.

Quantification of Optical Coherence Tomography Features in >3500 Patients with Inherited Retinal Disease Reveals Novel Genotype-Phenotype Associations.

PURPOSE: To quantify spectral-domain optical coherence tomography (SD-OCT) images cross-sectionally and longitudinally in a large cohort of molecularly characterized patients with inherited retinal disease (IRDs) from the UK. DESIGN: Retrospective study of imaging data. PARTICIPANTS: Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone macular SD-OCT imaging at Moorfields Eye Hospital (MEH) between 2011 and 2019. We retrospectively identified 4,240 IRD patients from the MEH database (198 distinct IRD genes), including 69,664 SD-OCT macular volumes. METHODS: Eight features of interest were defined: retina, fovea, intraretinal cystic spaces (ICS), subretinal fluid (SRF), subretinal hyper-reflective material (SHRM), pigment epithelium detachment (PED), ellipsoid zone loss (EZ-loss) and retinal pigment epithelium loss (RPE-loss). Manual annotations of five b-scans per SD-OCT volume was performed for the retinal features by four graders based on a defined grading protocol. A total of 1,749 b-scans from 360 SD-OCT volumes across 275 patients were annotated for the eight retinal features for training and testing of a neural-network-based segmentation model, AIRDetect-OCT, which was then applied to the entire imaging dataset. MAIN OUTCOME MEASURES: Performance of AIRDetect-OCT, comparing to inter-grader agreement was evaluated using Dice score on a held-out dataset. Feature prevalence, volume and area were analysed cross-sectionally and longitudinally. RESULTS: The inter-grader Dice score for manual segmentation was ≥90% for retina, ICS, SRF, SHRM and PED, >77% for both EZ-loss and RPE-loss. Model-grader agreement was >80% for segmentation of retina, ICS, SRF, SHRM, and PED, and >68% for both EZ-loss and RPE-loss. Automatic segmentation was applied to 272,168 b-scans across 7,405 SD-OCT volumes from 3,534 patients encompassing 176 unique genes. Accounting for age, male patients exhibited significantly more EZ-loss (19.6mm 2 vs 17.9mm 2 , p<2.8×10 -4 ) and RPE-loss (7.79mm 2 vs 6.15mm 2 , p<3.2×10 -6 ) than females. RPE-loss was significantly higher in Asian patients than other ethnicities (9.37mm 2 vs 7.29mm 2 , p<0.03). ICS average total volume was largest in RS1 (0.47mm 3 ) and NR2E3 (0.25mm 3 ), SRF in BEST1 (0.21mm 3 ) and PED in EFEMP1 (0.34mm 3 ). BEST1 and PROM1 showed significantly different patterns of EZ-loss (p<10 -4 ) and RPE-loss (p<0.02) comparing the dominant to the recessive forms. Sectoral analysis revealed significantly increased EZ-loss in the inferior quadrant compared to superior quadrant for RHO (Δ=-0.414 mm 2 , p=0.036) and EYS (Δ=-0.908 mm 2 , p=1.5×10 -4 ). In ABCA4 retinopathy, more severe genotypes (group A) were associated with faster progression of EZ-loss (2.80±0.62 mm 2 /yr), whilst the p.(Gly1961Glu) variant (group D) was associated with slower progression (0.56 ±0.18 mm 2 /yr). There were also sex differences within groups with males in group A experiencing significantly faster rates of progression of RPE-loss (2.48 ±1.40 mm 2 /yr vs 0.87 ±0.62 mm 2 /yr, p=0.047), but lower rates in groups B, C, and D. CONCLUSIONS: AIRDetect-OCT, a novel deep learning algorithm, enables large-scale OCT feature quantification in IRD patients uncovering cross-sectional and longitudinal phenotype correlations with demographic and genotypic parameters.

Economic evaluation of caregiver interventions for children with developmental disabilities: A scoping review.

Globally, families with children with developmental disabilities (DDs) experience challenges, including social isolation, stigma, and poverty, especially in low-income settings in Africa. Most children with DDs in Africa remain unidentified and receive no formal support. Caregiver interventions focusing on education and training for the carers/parents have been shown to be adaptable and low intensity in implementation, although the economic evidence is limited. This review aimed to describe the evidence and methodological aspects of economic evaluations for caregiver interventions for DDs. The Arksey and O'Malley framework was applied. Seven electronic databases, grey literature and cited references were systematically searched to identify eligible studies. published from 1993 to 2023. We assessed the quality of the included studies using the Drummond checklist. Data were systematically extracted, tabulated, and qualitatively synthesised using inductive thematic analysis. From 7811 articles, twenty studies all in high-income countries were included, and focused on caregiver interventions for autism spectrum disorder (n = 7), attention deficit hyperactivity disorder (ADHD) (n = 6), disruptive behaviour and behaviour problems with ADHD (n = 5), intellectual disabilities (n = 1) and language delay (n = 1). Economic evaluation analyses included cost effectiveness (n = 11), costing (n = 3), cost utility (n = 2), cost consequence (n = 1) cost benefit (n = 1), and combined analyses (n = 2). Nine studies reported the interventions as cost effective and five studies reported the intervention to be cost saving. The main methodological challenges were related to costing, outcome measurement in children and the appropriate time horizon for modelling. Caregiver interventions demonstrate cost-effectiveness, with the available evidence supporting the adoption of the interventions as a promising avenue to strengthen access and reduce the associated healthcare costs. The identified key methodological challenges highlighted further research areas. Prioritizing more economic evaluation studies in this area would inform decision-making on efficient resource allocation, promote inclusivity and equitable access to services for children with DDs.

Target selection signals causally influence human perceptual decision making.

The ability to form decisions is a foundational cognitive function which is impaired across many psychiatric and neurological conditions. Understanding the neural processes underpinning clinical deficits may provide insights into the fundamental mechanisms of decision making. The N2c has been identified as an EEG signal indexing the efficiency of early target selection, which subsequently influences the timing of perceptual reports through modulating neural evidence accumulation rates. Evidence for the contribution of the N2c to human decision making however has thus far come from correlational research in neurologically healthy individuals. Here, we capitalised on the superior temporal resolution of EEG to show that unilateral brain lesions in male and female humans were associated with specific deficits in both the timing and strength of the N2c in the damaged hemisphere, with corresponding deficits in the timing of perceptual reports contralaterally. The extent to which the N2c influenced clinical deficits in perceptual reporting speed depended on neural rates of evidence accumulation. This work provides causal evidence that the N2c indexes an early, hemisphere-specific process supporting human decision making. This non-invasive EEG marker could be used to monitor novel approaches for remediating clinical deficits in perceptual decision making across a range of brain disorders.Significance Statement Understanding how particular brain processes contribute to decision-making is crucial for our treatment of psychiatric and neurological disorders. This study provides causal evidence linking deficits in speed of visual processing to specific well-delineated EEG signals representing early target selection and evidence accumulation, in individuals with brain lesions. By showing how these lesions disrupt perceptual decisions, this work identifies a potential biomarker for decision-making deficits. This EEG measure offers a promising, non-invasive tool to track and refine treatments aimed at restoring decision-making abilities in affected patients.

Oral glucocorticoids and risk of psychiatric and suicidal behaviour outcomes: population-based cohort study.

BACKGROUND: Despite evidence of associations between glucocorticoid treatment and adverse psychiatric and suicidal behaviour outcomes, large-scale observational evidence for serious outcomes is lacking. AIMS: To assess the risk of psychiatric and suicidal behaviour outcomes during glucocorticoid treatment. METHOD: Using Swedish population registers, we identified 1 105 964 individuals aged 15-54 years who collected a glucocorticoid prescription in oral form between 2006 and 2020. We investigated associations with a range of psychiatric outcomes: unplanned specialist healthcare contacts due to depressive, bipolar, anxiety or schizophrenia-spectrum disorders; and deaths by suicide or unplanned specialist healthcare contacts due to self-harm ('suicidal behaviour'). We estimated hazard ratios from Cox proportional hazards models in a medication-only cohort by comparing outcome rates during and outside treated periods within individuals. We further identified individuals with an autoimmune or gastrointestinal autoimmune disorder diagnosis and compared hazards of the outcomes between those who did and did not initiate a glucocorticoid using a target trial emulation approach. RESULTS: We found increased risks for psychiatric outcomes, with within-individual hazard ratios ranging from 1.08 (95% CI, 1.00-1.16) for depressive disorders to 1.23 (95% CI, 1.12-1.36) for bipolar disorder and 1.25 (95% CI, 1.20-1.31) for anxiety disorders. We found no clear association with suicidal behaviour (hazard ratio: 1.06; 95% CI, 0.96-1.17). These findings were similar when stratified by age and gender. Within-individual associations were attenuated in those diagnosed with an autoimmune disorder. The risk of anxiety and bipolar disorder outcomes appeared particularly elevated in the first weeks of treatment. Absolute rates were modestly elevated during treatment, and higher in those with a history of psychiatric disorders. CONCLUSIONS: Glucocorticoid treatment is associated with elevated risks of serious psychiatric outcomes, including the onset and relapse of common psychiatric disorders. Individuals with psychiatric histories may require additional monitoring during glucocorticoid treatment.

The prevalence of prolonged grief disorder according to the international classification of diseases 11: a scoping review

Background: The eleventh revision of the International Classification of Diseases (ICD-11) introduces Prolonged Grief Disorder (PGD) as a new diagnostic category. This paper summarizes methodological approaches and prevalence estimates of studies on PGD in ICD-11. Methods: This review follows the JBI Manual of Evidence Synthesis and PRISMA-ScR guidelines. We searched MEDLINE, Embase, Web of Science, and PsycINFO (2011–2024), along with grey literature sources (Web of Science, Science.gov, NDLTD Global ETD Search). Included studies were cross-sectional or longitudinal, evaluating PGD prevalence using ICD-11 criteria. Two reviewers (KN, SK) independently screened studies, with a third (SG) resolving disagreements. Methodological quality was not assessed. Data extraction covered bibliographic details, study period, location, sample characteristics, diagnostic tools, algorithms, and prevalence. Results: Of 124 screened records, 35 studies were included in a qualitative synthesis. Seven main study categories emerged, primarily bereaved adults and representative national samples. Of 46 study samples, 24 were from Europe, followed by North America (n = 10) and Asia (n = 5), with none from South America. The PG-13 was the most commonly used tool, often omitting and raising ICD-11 PGD criteria simultaneously. ICD-11 PGD prevalence ranged from 1.5 to 15.3% in bereaved adults and 9.9–11.4% in national samples. Conclusions: Findings reveal heterogeneous study populations but limited geographic diversity. Standardized PGD assessments aligned with ICD-11 criteria, using tools specifically designed for ICD-11, along with detailed sample reporting, are needed to improve study comparability and consistency of prevalence. Important gaps by geographical and demographic groups remain.

In Children, N-Methyl-D-Aspartate Receptor Antibody Encephalitis Incidence Exceeds That of Japanese Encephalitis in Vietnam.

BACKGROUND: The recognition of autoimmune causes of encephalitis has led to epidemiological shifts in the worldwide characteristics of encephalitis. N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis leads to well-established complex neuropsychiatric manifestations. In low- and middle-income countries, including Vietnam, its relative incidence, especially in children, is unknown and most neurologists currently consider infectious encephalitis prior to autoimmune etiologies. METHODS: The study was prospectively conducted at Children's Hospital 1 in Ho Chi Minh City between March 2020 and December 2022. Any child admitted to the Department of Infectious Diseases and Neurology fulfilling the case definition of encephalitis was eligible to participate. Cerebrospinal fluid samples were collected alongside meta-clinical data for analysis. RESULTS: We recruited 164 children with a clinical diagnosis of encephalitis. Etiologies were determined as NMDAR antibody encephalitis in 23 of 164 cases (14.0%), Japanese encephalitis virus in 14 of 164 (8.5%), and herpes simplex virus in 4 of 164 (2.4%). Clinical categorizations suggested idiopathic viral encephalitis in another 71 (43.3%), and autoimmune encephalitis of unknown origin in the remaining 52. Factors including demographics, specific clinical features, cerebrospinal fluid and electroencephalogram findings, and length of hospital stay were significantly different between NMDAR antibody encephalitis and Japanese encephalitis. CONCLUSIONS: At a tertiary children's hospital in Vietnam, the prevalence of NMDAR antibody encephalitis exceeds that of Japanese encephalitis, the most common infectious encephalitis cause in Southeast Asia. NMDAR antibody encephalitis is associated with long hospital stay and poor outcomes. These findings should change pediatric diagnostics, to earlier consider autoimmune treatments in this clinical setting.

The murine ATP-binding cassette transporter C5 (Abcc5/MRP5/cMOAT) plays a role in memory consolidation, circadian rhythm regulation and glutamatergic signalling.

ATP-Binding cassette (ABC) transporters are a family of integral membrane ATPases that transport a large number of structurally unrelated compounds. The physiological role of the orphan transporter Abcc5 remains poorly understood. As previous work demonstrated that the loss of Abcc5 activity leads to elevated levels of NAAG in the brain, the impact of Abcc5 ablation was ascertained using behavioural phenotyping, circadian rhythm analysis and electrophysiological recordings of brain slices from Abcc5-/- mice and compared to wild-type littermates. Behavioural phenotyping of Abcc5-/- mice shows that the loss of murine Abcc5 activity results in profound changes in pre-pulse inhibition (PPI) as well as altered memory consolidation. Circadian measures of activity showed a delay in the timing of Abcc5-/- mice activity rhythm peak. Additionally, activity defined sleep analysis highlighted differences in sleep patterns in Abcc5-/- mice compared to wild-type controls. Patch clamp recording from pyramidal cells in the 2/3 layer of the frontal cortex showed altered synaptic AMPA/NMDA receptor current ratios and increased frequency of spontaneous excitatory postsynaptic currents (sEPSC). This study demonstrates that the loss of functional Abcc5 transporters does have behavioural consequences in mammals and alters NMDA receptor activity. These results highlight a previously unknown role of Abcc5 in the brain.

New suicide prevention guidance in England.

Call up the (cognitive) reserves: how adult socialisation and education influences cognition in the UK Biobank.

INTRODUCTION: Dementia involves the loss of memory and degradation of cognitive function. Crucially, the onset of dementia may be prevented by identifying and modifying relevant risk factors years before disease onset in midlife. Commonly described modifiable risk factors include social isolation and educational attainment. Here, we aim to understand the relationships between adult activities and their effects on cognition related to mid-life aging in terms of where and how people live. METHODS: We analysed data from the UK Biobank (N = 502,165, Mage = 56.53, SDage = 8.09, 54.40% female). In particular, our path analysis investigated the associations between years of education in childhood, education later in life, social activities in adulthood, built environment (i.e., coastal distance and percentage of greenspace), socioeconomic status (i.e., Townsend deprivation index), and cognitive functions (i.e., memory, executive function, and abstract reasoning). RESULTS: Adult education and social activities predict better cognition. Being deprived predicts attendance in adult education classes, but fewer social activities and poorer cognition. Moreover, living in areas with less greenspace and being further away from coastlines predict attendance in adult education classes; however, only greenspace predicts participation in social activities. Finally, less greenspace and further coastal distance support abstract reasoning, whereas further coastal distance predicts poorer executive function. CONCLUSION: We demonstrate the potential utility of adult education and social activities which may offset the detrimental effects of deprivation. Accordingly, we argue for improved access to adult social programs in deprived/underserviced areas in the United Kingdom.