Ultra-processed food (UPF) consumption has increased substantially among children worldwide and has been associated with early cardiovascular alterations. We aimed to identify plasma metabolomic profiles associated with UPF consumption in children aged 3-6 years and to assess their association with cardiovascular risk factors.

This cross-sectional analysis used baseline data from the Childhood Obesity Risk Assessment Longitudinal Study (CORALS), with children recruited between March 2019 and June 2022 through primary schools and health-care centres in seven Spanish cities. 1148 children were included (mean age 5.0 years [SD 1.1]; 50.6% girls) after exclusions due to medical conditions and incomplete or implausible dietary or metabolomic data. Energy-adjusted UPF intake (g/d) was assessed using a validated food frequency questionnaire and categorised with NOVA classification. 249 metabolites were quantified by NMR-based metabolomics, and lipid-related and amino acid-related profiles/scores were derived. A composite cardiovascular risk score (CVRs) was constructed by summing sex-specific, age-adjusted z-scores for fat-mass index, HDL-and LDL-cholesterol, triglycerides, mean arterial pressure, and Homoeostatic Model Assessment for Insulin Resistance.

19 metabolites were associated with UPF consumption after false discovery rate correction (FDR). A lipid-related score was positively associated with CVRs (β = 0.511; 95% CI: 0.413-0.610; FDR <0.001) and the amino acid-related score was associated with a lower CVRs (β = -0.494; 95% CI: -0.667 to -0.321; FDR <0.001). Discrimination of cardiovascular risk beyond covariates alone was higher after inclusion of metabolomic scores, particularly when both scores were considered jointly (ΔAUC 0.092, 95% CI: 0.013-0.172; p = 0.020).

In Spanish pre-schoolers UPF-related metabolomic profiles were associated with different cardiovascular risk factors. These diet-related metabolomic scores capture biological correlates relevant to early cardiovascular health and align with early-life metabolic pattering, supporting future longitudinal studies and prevention strategies.

CIBEROBN; Instituto de Salud Carlos III (ISCIII-FIS; EU ERDF/ESF); ISCIII PFIS.

Alagille syndrome (ALGS) is an autosomal dominant multisystem developmental disorder associated with JAG1 and NOTCH2 mutations. Although vascular involvement is recognized, life-threatening intracranial hemorrhage as the initial presentation is extremely rare.

A 5-year-old male presented with a severe headache and was diagnosed with intracerebral and subarachnoid hemorrhage caused by multiple ruptured intracranial aneurysms. Genetic testing confirmed a pathogenic JAG1 mutation, establishing the diagnosis of ALGS. The patient, who had known aortic stenosis, developed infective endocarditis-raising the possibility that infection was driving the aneurysms. After two microsurgical craniotomies, he ultimately died of multi-organ failure.

This case highlights a rare presentation of ALGS involving acute rupture of multiple intracranial aneurysms, complicated by cardiac malformation and infective endocarditis, with newly formed aneurysms highly suspected to be infection-driven. ALGS should be considered in young children presenting with early intracranial hemorrhage, particularly when cardiac anomalies coexist. Early multidisciplinary intervention may prevent the catastrophic sequelae of ALGS-associated intracranial aneurysms.

Macrophages play a critical role in regulating kidney injury and repair. Arginase 1 (ARG1), a key enzyme in L-arginine metabolism, is predominantly expressed in macrophages in injured kidneys. Polyamines derived from L-arginine metabolism promote the resolution of tissue injury. Follistatin-like 3 (FSTL3) is a secreted protein that acts as an antagonist of activins. However, its role in the kidney remains unknown.

To study this, serum FSTL3 levels were measured in patients with chronic kidney disease (CKD) or acute kidney injury (AKI) using ELISA. Kidney injury was induced by folic acid or cisplatin in mice. Bone marrow-derived macrophages (BMDMs) were isolated from Smad3 knock out mice. Bulk RNA-seq analysis was performed on injured kidneys and BMDMs. L-arginine metabolites were analyzed with liquid chromatography-mass spectrometry.

Serum FSTL3 levels were elevated in patients with CKD or AKI and were negatively correlated with estimated glomerular filtration rate and positively correlated with serum creatinine levels in CKD. Deletion of Fstl3 in mice ameliorated kidney injury and fibrosis, and this protective effect was associated with increased SMAD3 phosphorylation and ARG1 expression in macrophages. RNA-seq analysis revealed that arginine metabolism was highly enriched in the injured kidneys of Fstl3 knock out mice, as well as in BMDMs treated with activin A and IL-4. In vitro, activin A drastically synergized with the Th2 cytokines IL-4 and IL-13 to stimulate the expression of Arg1, along with Slc7a2 (also known as Cat2) and glycine amidinotransferase (Gatm), two other key genes involved in L-arginine metabolism, in macrophages, leading to enhanced L-arginine metabolism and polyamine production. Following folic acid treatment, Fstl3 knock out mice exhibited reduced tubular cell apoptosis and increased tubular cell proliferation.

Our results uncover a previously unrecognized role for activin signaling in the regulation of L-arginine metabolism in macrophages. Fstl3 deletion activates this metabolism, thereby facilitating the resolution of kidney injury.

Ferulic acid (FA), a key bioactive compound extracted from Angelica sinensis- traditionally used in herbal medicine, is now widely used as nutritional supplements and therapeutic agent for the management of cardiovascular diseases in which oxidative stress and autophagy dysregulation contribute significantly to disease progression.

This study aimed to investigate the protective effects and underlying mechanisms of FA against oxidative stress using both an in vivo transient middle cerebral artery occlusion (MCAO) rat model and an in vitro oxygen-glucose deprivation (OGD) model in PC12 cells.

Male Sprague-Dawley rats (180-220 g) subjected to transient MCAO received intraperitoneal FA (25, 50, or 100 mg/kg) once daily for five consecutive days. 50 mg/kg was identified as the lowest effective dose and used for subsequent mechanistic studies. Neurological function, infarct volume, oxidative stress, and autophagy-related markers were assessed in FA-treated and untreated animals. In OGD-exposed PC12 cells, RNA interference and Western blotting were used to investigate the molecular mechanisms underlying FA-mediated regulation of oxidative stress and autophagy.

FA significantly reduced cerebral infarct volume, brain edema, and neurological deficit scores in MCAO rats. FA attenuated oxidative stress by decreasing reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) levels and enhancing the expression of key antioxidant mediators, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), manganese superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD), and glutathione (GSH). FA also modulated autophagic markers in ischemic brain tissue, as evidenced by a reduced LC3-II/LC3-I ratio and increased p62 expression. FA significantly improved cell viability, increased GSH levels, reduced intracellular ROS accumulation, upregulated antioxidant protein expression, and inhibited autophagy in OGD-induced PC12 cells. siRNA-mediated knockdown of Nrf2 partially abolished the antioxidative and autophagy-modulating effects of FA.

FA may protect against ischemic brain injury through Nrf2-dependent enhancement of antioxidant defenses and modulation of autophagy, highlighting its potential as a promising therapeutic candidate for the development of novel neuroprotective interventions.

Programmed cell death factor 4 (PDCD4) has been implicated in various metabolic disorders. However, its role and underlying mechanisms in metabolic dysfunction-associated steatotic liver disease (MASLD) have not been fully elucidated.

This study aimed to define the role of PDCD4 in hepatic steatosis and identify potential therapeutic strategies targeting its downstream metabolic pathway.

RNA sequencing was performed on liver tissues from wild-type and PDCD4-knockout mice to identify dysregulated metabolic pathways and candidate downstream genes. The PDCD4-HNF4A-GK regulatory pathway was investigated using genetic, histological, biochemical, and molecular analyses in mouse models and hepatocytes. Virtual screening and molecular docking were used to identify candidate GK-targeting compounds.

Hepatocyte-specific PDCD4 deletion increased hepatic GK expression and aggravated lipid accumulation. GK knockout markedly attenuated PDCD4 deficiency-induced lipid accumulation in hepatocytes. Mechanistically, PDCD4 suppressed HNF4A translation, thereby limiting HNF4A-dependent GK transcription. Virtual screening identified isosinensetin as a candidate GK inhibitor. Isosinensetin inhibited GK activity and reduced lipid accumulation in hepatocytes and CDAHFD-fed mice.

These results suggest that GK may warrant further investigation for ameliorating hepatic steatosis, and provide preliminary evidence for the PDCD4-HNF4A-GK axis in the regulation of hepatic triglyceride metabolism. Further studies are required to establish the relevance of this axis to the full spectrum of MASLD pathology.

Transoral endoscopic thyroidectomy via the vestibular approach (TOETVA) provides excellent cosmetic outcomes but introduces specific anatomical challenges related to the mental nerve. Although the location of the mental foramen has been extensively studied, detailed information regarding the extraosseous course, branching pattern, and layer-based relationships of the mental nerve remains limited. This study aimed to characterize the extraosseous anatomy of the mental nerve in fresh-frozen Vietnamese cadavers and provide anatomical information relevant to vestibular incision planning and trocar placement in TOETVA.

A descriptive anatomical study was performed on 15 fresh-frozen Vietnamese adult cadavers, providing 30 mental nerves for analysis. The mental foramen and extraosseous mental nerve branches were dissected systematically. Morphometric parameters, branching patterns, and relationships between nerve branches and surrounding soft tissue layers were recorded.

The mental foramen was most commonly located in line with the second premolar (50.0%). The mental nerve divided early after exiting the foramen, with a mean distance to the first branching point of 3.17 ± 2.55 mm. Branching patterns showed considerable variability, with all five Hu classification types observed and side-to-side asymmetry present in 46.7% of cadavers. After exiting the foramen, the mental nerve was consistently superficial to the periosteum. The angular and lateral inferior labial branches coursed deep to the orbicularis oris muscle in all specimens, while the mental branch most commonly followed a superficial course relative to the mentalis muscle.

The mental nerve demonstrates early extraosseous branching and consistent layer-based anatomical relationships after exiting the mental foramen. These findings provide important anatomical information relevant to vestibular incision planning and trocar placement in TOETVA.

The human brain undergoes profound changes from early development through late adulthood, shaping cognition, behaviour and vulnerability to disease^1,2. Understanding how these changes are organized within specific brain regions and cell types is essential for interpreting normal ageing and its relationship to psychiatric and neurodegenerative disorders. The dorsolateral prefrontal cortex has a central role in higher cognitive functions and is particularly sensitive to age-related decline³, yet its cellular and molecular programs across the human lifespan remain poorly defined. Most existing studies^4-7 have focused on restricted age ranges or disease-affected brains, limiting the ability to distinguish normative developmental and ageing trajectories from pathological processes. Consequently, a comprehensive, lifespan-resolved reference of cellular states in the human prefrontal cortex has been lacking. Here, using a single-nucleus transcriptomic atlas spanning the human lifespan, we show that the dorsolateral prefrontal cortex exhibits non-linear, cell-type-specific transcriptional trajectories characterized by dynamic remodelling during development, relative stability in midlife and selective molecular reactivation in late adulthood. We identify distinct neuronal and glial programs, including early-life neuronal resilience pathways and late-life glial programs associated with immune activation, stress responses and circadian reorganization. These programs are anatomically organized across cortical layers and grey-white matter domains, revealing coordinated spatial and molecular changes. Together, these findings provide a framework for understanding how cellular programs transition from resilience to vulnerability in the human cortex and establish a foundation for interpreting age-related cognitive decline and disease risk.

Individuals with severe to profound intellectual disability (ID) exhibit high support needs and significant communication impairments and may present with challenging behaviours such as aggression, self-injury and stereotypies. These behaviours can cause distress, hinder healthcare access and delivery and impair quality of life for affected individuals and caregivers. Despite their prevalence and impact, empirical research often excludes this group due to methodological and ethical challenges.

This systematic review aimed to identify and synthesise published evidence on factors associated with challenging behaviours in individuals with severe to profound ID.

We systematically searched six databases (Embase, Medline, Cinahl, PsycINFO, ERIC and Cochrane Library) for studies from January 2009 until March 2023. Eligible publications, original research or systematic reviews, required ≥ 25% severe/profound ID in the sample and focused on challenging behaviours plus associated factors. Quality was assessed using NIH observational study criteria.

Of 2672 records screened, 31 studies met inclusion criteria. Narrative synthesis revealed that self-injurious behaviour, aggression and stereotypy were the most frequently studied topographies, with limited research on sleep and eating disturbances. Consistent associations emerged between communication deficits (particularly expressive speech) and both aggressive and self-injurious behaviour (three studies). Overactivity, impulsivity and repetitive behaviours were also correlates for self-injurious behaviour and aggression (five studies). Adaptive functioning was inversely associated with all major topographies, whereas comorbid autism was directly associated (two and eight studies). Other personal/medical factors (sex, age, ability level, medical issues, etc.) and contextual/psychosocial factors (social skills, mood, setting, etc.) showed inconsistent or no associations.

Challenging behaviours in individuals with severe to profound ID are multifactorial, with communication and adaptive functioning deficits, repetitive and impulsive behaviours, and comorbid autism symptoms as key associated factors. Strengthening assessments of communicative and adaptive skills, and addressing modifiable behavioural and environmental correlates, can inform tailored interventions. However, the current evidence base is limited by methodological heterogeneity and underrepresentation, which has also impeded conducting meta-analysis or risk of bias assessment. Future studies should use longitudinal designs, syndrome-specific analyses and improved measurement of contextual variables.

The Early Psychosis Intervention Network (EPINET) funded by the National Institute of Mental Health includes 111 early psychosis programmes across the United States. This investigation examines the prevalence of peer support and family peer support within CSC programmes. We describe the settings in which peer support and family peer support are offered, as well as other contextual factors (such as policies and funding mechanisms) associated with offering peer support and family peer support.

A programme-level measure was used to capture services, the location of service delivery and funding for services at one timepoint. These data were linked with external state-level data to examine whether state policies were associated with offering peer support and family peer support.

Most programmes (80%) offered peer support services and 59% offered family peer support. The findings suggest that availability of funding sources and support on the state level may facilitate CSC programmes offering peer support and family peer support.

Although peer support and family peer support were not originally conceptualized as core CSC services, currently most CSC programmes in the United States offer peer support and more than half also offer family peer support, suggesting the need for more research to understand variations in service delivery and impact on outcomes.