To assess the impact of cardiorespiratory fitness (CRF) and muscle strength on depression and individual depression symptoms. Mendelian randomisation (MR) analysis was conducted in up to 341,326 participants of European ancestry from UK Biobank (aged 37-73years). Genetic variants from previous genome-wide association studies (GWAS) of CRF and grip strength (to proxy overall muscle strength) were utilised to instrument exposures. A broad depression phenotype based on self-report and hospital records, as well as individual measures of depression symptoms from the Patient Health Questionnaire-9 (PHQ-9) were used as outcomes. Analysis was repeated stratifying by sex and using summary statistics from a major depressive disorder (MDD) GWAS. There was no clear evidence for association between CRF and any depression outcome. There was robust evidence suggesting greater grip was associated with lower odds of broad depression (OR per 0.1kg increase in weight adjusted grip: 0.86, 95% CI:0.80,0.93), as well as the PHQ-9 items appetite changes (OR:0.56, 95% CI:0.49,0.65), and anhedonia (OR:0.79, 95% CI:0.69,0.90), a core symptom of depression. There was also some evidence for associations between greater grip and lower odds of depressed mood (OR:0.85, 95% CI:0.74,0.97), psychomotor changes (OR:0.79, 95% CI:0.64,0.97), fatigue (OR:0.83, 95% CI:0.74,0.93) and concentration problems (OR:0.85, 95% CI:0.74,0.98) in the MR-inverse variance weighted analysis. Effects were mostly driven by stronger associations in females and results replicated in the two-sample MR for MDD. Muscle strength may represent an important modifiable factor for preventing and treating depression and several specific symptoms, including core symptoms such as anhedonia.

Achondroplasia (ACH), the most common skeletal dysplasia, arises from gain-of-function variants in the fibroblast growth factor receptor 3 gene. Children with ACH experience lifelong medical, functional and psychosocial challenges requiring coordinated and anticipatory care. Although international guidance exists, the UK lacks national clinical care recommendations specific to its healthcare systems. To develop UK-specific, multidisciplinary clinical recommendations for the care of children and young people (CYP) with ACH. The UK Achondroplasia Network developed guidance in stages: stakeholder mapping of the care pathway, integration of contemporary literature with clinical expertise to draft age-specific guidance and Delphi statements, and a modified Delphi process with 25 multidisciplinary experts. The Delphi process involved two voting rounds and an in-person meeting, with consensus defined as ≥80% agreement. In the first Delphi round, all 20 statements achieved consensus; nine achieved 100% agreement. To strengthen consensus, after meeting in person, 17 statements were refined (four were divided into two statements), one created and one removed, resulting in 24 statements for Round 2; all achieved consensus, with 21 reaching 100% agreement. The guidance outlines age-specific monitoring and referral from infancy to adolescence. Recommendations address medical management of complications, psychosocial support, educational planning and transfer to adult care. These are the first UK-specific multidisciplinary recommendations for the care of CYP with ACH. Aligned with international best practices and tailored to UK healthcare systems, they support anticipatory care, promote independence and enhance health and psychosocial outcomes. The guidelines offer a foundation for service planning, standardisation and equitable care.

BackgroundThe clinical and prognostic implications of asymptomatic tuberculosis remain poorly understood.MethodsWe conducted a multicentre prospective cohort study to evaluate the association between asymptomatic tuberculosis (TB) and treatment outcomes. Individuals with rifampicin-susceptible pulmonary TB were enrolled from the Cohort Study of Pulmonary Tuberculosis. Asymptomatic TB was defined as the absence of any TB-related symptoms at diagnosis. The primary outcome was a favourable outcome, defined as treatment success without recurrence. Multivariable logistic regression models were used to assess associations between asymptomatic TB and favourable outcomes. The Cox proportional hazards model was applied to evaluate effect of asymptomatic TB on failure to complete treatment within 1 year. Stratified analyses by symptom status and mode of detection were performed to examine stratum-specific effects.ResultsOf 1071 individuals with pulmonary TB, 32.7% were asymptomatic. Compared to symptomatic patients, asymptomatic individuals were younger, less likely to be underweight and more often diagnosed through population health screening rather than clinical presentation or opportunistic testing. Asymptomatic TB was associated with higher likelihood of favourable outcome in multivariable models (adjusted odds ratio (aOR) 1.50, 95% CI 1.04–2.20) and a reduced risk of failing to complete treatment within one year in survival analyses (adjusted hazard ratio 0.66, 95% CI 0.45–0.95). Asymptomatic TB detected through health screening had the most favourable outcomes (aOR 2.41, 95% CI 1.34–4.66).ConclusionAsymptomatic TB was significantly associated with treatment success without recurrence and particularly in patients identified through health screening. Our results support symptom-agnostic screening in TB control programmes.

Trained immunity is the ability of the innate immune system to mount a heightened response to an environmental stimulus after a previous encounter with a noxious trigger. This effect is mediated by metabolic rewiring and epigenetic reprogramming in innate immune cells. In the context of neuroinflammation, trained immunity may represent a major contributor to the pathogenesis of neurological diseases, exerting both detrimental and potentially beneficial effects. While the general mechanisms and systemic implications of trained immunity are widely discussed, evidence in central nervous system (CNS) diseases remains fragmented and largely confined to individual pathological conditions. As a result, a comprehensive framework integrating these findings and identifying shared mechanisms across neurological disorders is still lacking. In this review, we explore the concept of trained immunity with a focus on neuroinflammatory and neurodegenerative diseases, synthetizing evidence from multiple CNS pathologies, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and cerebrovascular disorders. We first critically examine preclinical and experimental studies addressing innate immune memory in the CNS and subsequently integrate these findings with emerging clinical evidence, aiming to identify convergent mechanisms and disease-relevant immune memory signatures. Finally, we discuss potential therapeutic targets identified in preclinical settings and outline key unresolved issues, including the nature of triggering stimuli, thresholds, and temporal dynamics shaping innate immune memory in the CNS. By highlighting current limitations and defining critical questions for future research, this review presents a unifying perspective on trained immunity in neurological diseases and underscores the translational potential to modulate neuroinflammation and to influence disease progression.

Neighbourhood socioeconomic disadvantage correlates with cardiovascular disease risk. However, its relationship with subclinical atherosclerosis from childhood to midlife is not well-defined. We examined whether cumulative neighbourhood disadvantage is associated with carotid artery plaques, a measure of subclinical atherosclerosis. We analysed data from 1998 participants in the Cardiovascular Risk in Young Finns Study, a cohort followed from childhood (mean age 10.7years in 1980) to adulthood (mean age 48.6years in 2018-2020). Neighbourhood disadvantage was derived from national grid-based socioeconomic data and computed cumulatively across the life course. The number of carotid artery plaques (mean plaque count) was assessed by standardized ultrasound imaging. Multivariable Poisson regression models were used to evaluate the associations. Mediation analyses were used to assessed the role of ideal cardiovascular health (CVH) metrics. Higher cumulative neighbourhood disadvantage from childhood to mid-adulthood was associated with a 1.24-fold increase in mean plaque count for every 1 standard deviation increase in cumulative disadvantage. This relationship persisted after controlling for parental carotid artery plaques, polygenic coronary artery disease risk score, and Framingham risk score. The association was partially explained by ideal CVH metrics, particularly smoking and blood pressure, which collectively accounted for almost half of the association. Long-term exposure to neighbourhood socioeconomic disadvantage beginning in childhood is associated with subclinical atherosclerosis in midlife, independently of achieved socioeconomic position. These findings highlight the importance of cumulative socioeconomic environments across the life course and suggest that behavioural risk factors may partly explain observed neighbourhood-level associations with atherosclerosis.

The authors declare no conflicts of interest.