AIMS/HYPOTHESIS: Nearly 40% of African adults with type 2 diabetes are lean (BMI <25 kg/m). Emerging evidence suggests that type 2 diabetes in African individuals who are lean may represent a distinct phenotype driven by impaired insulin secretion rather than insulin resistance, raising concerns about treatment mismatch and divergent disease outcomes. We examined complication profiles in Africans with type 2 diabetes who are lean vs overweight/obese. METHODS: We analysed harmonised, individual-level cross-sectional data from two large, well-characterised African cohorts (Africa America Diabetes Mellitus study, n=2790; Research on Obesity and Diabetes among African Migrants study, n=541; total n=3331) of adults with type 2 diabetes from Ghana, Nigeria and Kenya. Participants were classified as lean (BMI <25 kg/m) or overweight/obese (BMI ≥25 kg/m). Robust Poisson regression, adjusted for age, sex, education and treatment, assessed associations with retinopathy, chronic kidney disease, stroke, hypertension and 10-year cardiovascular disease risk. Cohort-specific estimates were pooled using random effects, followed by mediation analysis examining contributions of lifestyle and metabolic markers to observed differences. RESULTS: Type 2 diabetes in Africans who are lean was characterised by lower beta cell function and low insulin levels. Compared with individuals who are overweight/obese, adults who are lean showed a higher prevalence of retinopathy (pooled prevalence ratio [pPR] 1.36 [95% CI 1.13, 1.63]) and stroke (pPR 1.41 [95% CI 1.01, 1.99]), but lower hypertension (pPR 0.77 [95% CI 0.71, 0.85]) and 10-year cardiovascular disease risk (pPR 0.85 [95% CI 0.74, 0.97]). Chronic kidney disease prevalence did not differ between groups. Body fat percentage accounted for most differences (up to 92%). CONCLUSIONS/INTERPRETATION: Complication patterns in Africans with type 2 diabetes who are lean vs overweight/obese follow divergent paths. In Africa, where nearly 24 million people have type 2 diabetes, two-fifths of whom are lean, our findings add to growing evidence that lean type 2 diabetes may be a distinct phenotype, underscoring the urgent need for investigation into better-targeted management for this large, potentially mistreated, population.

BACKGROUND: Deep vein thrombosis (DVT) is a frequent yet underrecognized complication in critically ill patients with chronic obstructive pulmonary disease (COPD). Existing risk assessment tools are not specifically tailored to this high-risk population. We aimed to develop and externally validate an interpretable machine-learning model for early prediction of DVT in ICU-admitted COPD patients. METHODS: Adult COPD patients admitted to the ICU were identified from the MIMIC-IV database and randomly divided into training and internal validation cohorts. Eight machine-learning algorithms were constructed and compared. The best-performing model was externally validated in MIMIC-III and eICU cohorts. Model discrimination, calibration, and clinical utility were assessed using AUC, calibration plots, decision-curve analysis (DCA), and Brier scores. SHAP analysis was applied for global and individual interpretability. A web-based calculator was developed for clinical application. RESULTS: Among 6,672 ICU patients with COPD, 462 (6.9%) developed DVT. XGBoost showed the best overall performance, with an AUC of 0.840 (95% CI 0.812-0.868) in the internal validation cohort and good calibration. External validation confirmed stable discrimination in both MIMIC-III and eICU cohorts. Model interpretation identified prolonged PTT, elevated RDW, reduced SpO, and increased respiratory rate as important contributors to DVT risk. Decision-curve analysis suggested potential clinical benefit across relevant risk thresholds. CONCLUSION: We developed and externally validated an explainable machine-learning model for early prediction of DVT in ICU patients with COPD. By providing individualized risk estimates and interpretable explanations, this tool may help clinicians identify high-risk patients earlier and support more targeted thromboprophylaxis and imaging surveillance strategies.

A major focus of contemporary medical research is the primary pathological cardiovascular diseases, whereas stress-induced vascular senescence is a process with degenerative changes in vascular morphology, structure, and function caused by oxidative stress (OS), inflammation, autophagy disorders, and other factors. Silent information regulator of transcription 1 (SIRT1), which may be a key gene linking oxidative stress and aging, has extensive biological functions in anti-oxidation, anti-inflammation, anti-apoptosis, and other aspects. This paper focuses on the protective effects and main mechanisms of SIRT1 on stress-induced vascular senescence and provides clues for preventing and treating diseases related to stress-induced vascular senescence.

Recent medical advances have significantly improved the life expectancy of individuals with congenital heart disease (CHD); however, these children remain at increased risk of co-occurring neurodevelopmental disorders (NDD), such as attention-deficit/hyperactivity disorder and autism spectrum disorder. Although prenatal environmental factors, including placental dysfunction and altered oxygen levels in utero, as well as postnatal events such as cardiac surgery, may contribute to this increased risk, shared genetic factors may also underlie both conditions. Therefore, this study is aimed at investigating genomic, transcriptomic and epigenomic findings in patients with NDD and/or CHD using an integrative multiomic approach. A cohort of 14 trios and one duo was recruited: Two probands had both NDD and CHD, two had CHD only and 11 had NDD only. Blood samples were analysed using whole-genome sequencing, RNA sequencing and DNA methylation profiling. We identified one large deletion (~2.5 Mb) and seven likely pathogenic/pathogenic (LP/P) variants, including two in autosomal dominant genes relevant to the patients' phenotypes and five in autosomal recessive genes consistent with carrier status. This included a likely pathogenic de novo splice-disrupting variant in the chromatin remodelling gene , validated by RNA sequencing. DNA methylation analysis revealed epigenetic differences between CHD and NDD patients, with CHD patients showing elevated biological age acceleration. Comparison with a reference cohort of 178 controls identified four probands with extreme methylation dysregulation, including the individual with the variant. Overall, these findings highlight the diagnostic and mechanistic value of integrative multiomic profiling in paediatric developmental disease cohorts.

The effects of space radiation on clonal hematopoiesis (CH) and its impact on long-term health outcomes are unknown. Using male and female murine models of , -, and -mediated CH, we examined the effects of exposure to gamma radiation, simulated solar particle events, or simplified simulated galactic cosmic rays on the clonal expansion of mutant cells and long-term health outcomes. Radiation accelerated the expansion of and , but not , mutant clones. Over 18 months, male mice with mutant cells showed worse survival than controls, which was exacerbated following radiation exposure. The interaction between the mutation and radiation exposure was absent for the other driver genes and in female mice with mutations. Male mice with mutant cells exhibited evidence of hematologic disease and hematopoietic loss of the Y chromosome. Male astronauts with clonal hematopoiesis may be at elevated risk of clone growth and hematologic disease following radiation exposure.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder primarily caused by pathogenic variants in the gene, leading to clinical manifestations including pulmonary arteriovenous malformation (PAVM), recurrent spontaneous nosebleeds, and other related symptoms. This study is aimed at investigating the clinical manifestations of members in four HHT1 families with PAVMs and analyze novel variants. METHODS: Clinical evaluations, whole exome sequencing (WES), and Sanger sequencing were performed on the probands and their family members from Families 1 to 4. Bioinformatics programs were utilized to assess the pathogenicity of the candidate variants. Additionally, an in vitro minigene assay was conducted to examine the impact of the variant in Family 2 on RNA splicing, and Western blot was employed to validate the impact of the variant on protein expression and modification. RESULTS: Four variants were identified: c.613del (exon 5), c.1428 + 2 T > C (intron 11), c.1498dup (exon 12), and c.322del (exon 3). The splice-site variant c.1428 + 2 T > C, which has been reported as pathogenic in ClinVar, leads to aberrant mRNA splicing with exon 11 skipping, resulting in a shorter protein (p.Lys438_Gln476del) with impaired glycosylation. CONCLUSION: The splice-site variant c.1428 + 2 T > C caused aberrant ENG mRNA splicing, leading to exon 11 skipping and producing a shorter protein with abnormal glycosylation (p.Lys438_Gln476del). The variants identified in Families 1, 3, and 4 (c.613delC, c.1498dupC, and c.322delG) are all frameshift variants that lead to premature termination of translation. This study expands the spectrum of variants and provides insights into the pathogenesis of HHT1. These findings offer guidance for the early diagnosis for families affected by HHT1.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease worldwide and includes a spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis, and cirrhosis. Given the heterogeneous nature of disease progression and the central role of fibrosis predicting local or systemic clinical outcomes (e.g. liver cirrhosis, hepatocarcinoma, cardiovascular diseases), early identification and longitudinal monitoring of individuals at risk is crucial. However, current diagnostic tools present important limitations, particularly across diverse metabolic profiles such as individuals living with obesity or type 2 diabetes. Therefore, this review provides a comprehensive overview of current diagnostic and monitoring strategies for MASLD and MASH, including routine biochemical markers, noninvasive steatosis and fibrosis scores, imaging modalities, and liver biopsy. Multimodal and individualized diagnostic approaches integrating clinical, metabolic, imaging, and molecular data appear essential to improve early detection, refine longitudinal monitoring, and support precision-based management of MASLD.

Dyslipidemia is a significant risk factor for cardiovascular disease (CVD), the leading cause of death in Samoa. Polygenic scores (PGS) for lipid traits offer promise for improved CVD risk prediction; however, their performance in Pacific Islander populations - comprising only 0.002% of GWAS participants as of 2024 - remains unknown. We evaluated the transferability of multi-ancestry PGS for LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglycerides (TG), and total cholesterol (TC) in 4,342 Samoan adults across five cohorts spanning 1990-2010. PGS from Graham et al. and Kanoni et al. multi-ancestry meta-analyses were harmonized with genome-wide imputed genotypes using a Samoan-specific reference panel, and performance was assessed via incremental R from linear mixed models with bootstrapped confidence intervals. HDL-C showed the highest performance (incremental R 5.0-15.0%), followed by TC (5.0-10.7%), LDL-C (5.7-8.6%), and TG (3.5-7.0%). Critically, meaningful LDL-C performance was achieved only with the genome-wide PRS-CS score (99.6-99.7% variant matching), while a curated pruning-and-thresholding score achieved ∼9% matching and near-zero performance. These findings establish systematic lipid PGS benchmarks in Samoans, demonstrating meaningful transferability when genome-wide variant coverage is ensured, and highlight variant harmonization as a critical precondition for PGS deployment in underrepresented populations.

Acute kidney injury (AKI) affects approximately 15% of all hospitalized individuals and nearly half of those admitted to intensive care units and is increasingly recognized as a systemic syndrome whose consequences extend well beyond structural and functional changes confined to the kidney. Experimental studies highlight the role of inflammation and accumulation of metabolites as pivotal drivers in the cross-talk between the kidneys and distant organ systems during AKI. Whereas clinical data reveals an association between AKI and non-renal organ dysfunctions and complications. This review outlines the pathophysiological mechanisms underlying AKI-associated remote organ dysfunction, focusing on five key organ systems: the lungs, the brain, the heart, the liver and the immune system. We discuss the direct consequences of reduced kidney function alongside the repercussions of the inflammatory cascade triggered by kidney cell injury and the resulting clinical implications. Recognizing that multi-organ failure significantly influences patients' morbidity and mortality, identifying specific pathways of organ cross-talk is essential to optimize clinical management. Finally, we evaluate novel endpoints for future AKI trials. Given that traditional long-term metrics, such as Major Adverse Kidney Events (MAKE), present significant design challenges in non-enriched populations, we analyze alternative and surrogate outcomes, including those directly related to the remote organ complications of AKI.

INTRODUCTION: Compared with anti-citrullinated protein autoantibody (ACPA)-positive RA, the etiology of ACPA-negative RA remains unclear, posing significant challenges to diagnosis. Recently, evidence has emerged that ACPA-negative RA is characterized by metabolic reprogramming, as well as dysregulated lipid metabolism. The remnant cholesterol inflammation index (RCII) is a comprehensive index of lipid burden and inflammation; this study evaluated the predictive value of RCII as a novel biomarker for ACPA-negative RA. METHODS: In the Beijing Hospital (BJH) cohort, we first compared RCII across various autoimmune diseases and undifferentiated inflammatory arthritis versus healthy controls (HCs). Subsequently, we assessed the independent association between RCII and ACPA-negative RA in the BJH cohort and UK Biobank (UKB) cohort using multivariable logistic regression, adjusting for confounders including age, sex, BMI, and cardiovascular comorbidities. Diagnostic performance was evaluated via receiver operating characteristic (ROC) analysis, and optimal diagnostic RCII intervals were defined using a stratified 5-fold cross-validation framework. Furthermore, the possible underlying mechanisms were investigated using untargeted serum lipidomics in a matched subset. RESULTS: In the BJH cohort, RCII levels were significantly elevated in ACPA-negative RA, ACPA-positive RA, undifferentiated inflammatory arthritis, dermatomyositis, and systemic lupus erythematosus compared with HCs, with the highest levels observed in ACPA-negative RA. Dual-cohort analysis confirmed elevated RCII in ACPA-negative RA, with independent associations (BJH: OR = 26.11; UKB: OR = 5.59) even after adjusting for age, sex, BMI, and cardiovascular disease (CVD). In the ROC analysis, RCII demonstrated relatively high diagnostic accuracy, achieving an area under the curve (AUC) of 0.929 in the BJH cohort and 0.785 in the UKB cohort. Cross-validation established stable diagnostic intervals, effectively minimizing the indeterminate decision zone, or "gray zone" to less than 10% of cases. Lipidomic profiling revealed a possible metabolic signature characterized by the broad suppression of phosphatidylcholines (PCs) and triacylglycerols (TAGs) alongside the specific upregulation of pro-inflammatory ceramides (Cers), preliminarily providing biological plausibility for the lipid-inflammation interplay reflected by RCII. CONCLUSION: RCII served as an integrative biomarker, demonstrating improved diagnostic performance compared with isolated lipid or inflammatory measures in identifying ACPA-negative RA. By reflecting the metabolic-inflammatory burden, the interval-based RCII thresholds established in this study provided a practical tool with the potential to help address the current diagnostic gap in seronegative patients. Key Points • This dual-cohort study shows elevated RCII in ACPA-negative RA (median 3.13 vs 0.32 in BJH; 1.91 vs 0.64 in UKB, both P< 0.001) and independent associations after adjustment for age, sex, BMI, and CVD (OR 26.11 in BJH; OR 5.59 in UKB). • Stratified 5-fold cross-validation with reciprocal validation produced RCII diagnostic intervals (0.211-1.744 from BJH; 0.120-1.873 from UKB) that placed all cases in the positive interval while restricting the grey zone to 8.3-9.8% across cohorts. • Serum lipidomics in matched subsets (n = 25 per group) identified 64 differential lipids (61 downregulated, 3 upregulated), featuring reduced TAGs and PCs along with increased pro-inflammatory ceramides (e.g., Cer d18:1/18:0, FC = 1.91), preliminarily providing biological plausibility for the observed RCII elevations in ACPA-negative RA.

Chemokines are traditionally known for their roles in immune cell recruitment during inflammation, but emerging evidence suggests that they may also directly regulate cellular states within the central nervous system. Specifically, it remains unclear whether CXCL16 affects microglial functional states in ischemic stroke. Here, we demonstrated that recombinant CXCL16 (rCXCL16) modulated the expression of inflammation- and repair-associated markers in primary microglia and in the ischemic brain. Functionally, microglia pretreated with rCXCL16 increased HT-22 cell viability and reduced apoptosis in an indirect co-culture system. Consistently, in vivo administration of rCXCL16 reduced infarct size, restored neurobehavior performance, and suppressed apoptosis in experimental stroke in mice. These findings identify rCXCL16 as a modulator of microglial responses and suggest that its neuroprotective effects are associated with reduced inflammatory marker expression and attenuation of apoptotic injury after ischemic stroke.

Cerebral ischemia-reperfusion (I/R) injury continues to be a significant factor contributing to neuronal loss and functional deficits subsequent to ischemic stroke, predominantly driven by oxidative stress, neuroinflammation, and apoptosis. Spexin (SPX), a recently discovered neuropeptide, has emerged as a potential regulator of oxidative and inflammatory mechanisms; however, its role in cerebral I/R injury remains to be elucidated. This study investigated the neuroprotective effects of spexin in a rat model of cerebral I/R injury. Male Wistar rats were randomly assigned to the control, I/R, and I/R+SPX (50 µg/kg, subcutaneously) groups. Ischemia was induced by bilateral common carotid artery occlusion for 30 min followed by 24 h of reperfusion. Neurological, histological, and biochemical parameters were evaluated. I/R injury caused significant neuronal degeneration and necrosis in the prefrontal cortex (p < 0.001), along with increased lipid peroxidation, reduced glutathione levels (p < 0.001), and elevations in TNF-α and IL-6 levels (p < 0.05-0.001). These changes were associated with pronounced expression of NF-κB signaling and increased expression of the pro-apoptotic markers and Caspase-3 (p < 0.001). Spexin administration significantly attenuated neuronal damage, reduced MDA and proinflammatory cytokine levels, restored antioxidant capacity, and suppressed NF-κB immunoreactivity and apoptotic signaling (p < 0.05-0.001). These findings demonstrate that spexin attenuates cerebral I/R-induced brain injury by suppressing oxidative stress, NF-κB-associated inflammation, and apoptosis. Spexin may represent a promising therapeutic candidate for ischemic stroke-associated neuronal injury.

Cardiovascular laterality defects occur with an estimated birth prevalence of 1.1/10,000 live births, associated with congenital heart defects (CHD) and situs abnormalities. Known disease genes explain about 20% of all cases often correlated with primary ciliary dyskinesia (PCD). We aimed to identify disease genes beyond PCD-related aetiologies using exome sequencing in 16 case-parent trios followed by exome survey in 2,109 individuals with situs inversus totalis, heterotaxy, or isolated CHD. We identified six different variants in FAM222B, previously discussed as a candidate gene for cerebral cavernous malformations. The variant c.899G > A (p.300Arg > His) was found de novo in two unrelated families. FAM222B has been described as a substrate of Nemo-like kinase (NLK), associated with left-right body axis determination. Structural modelling suggests a function of FAM222B Arg300 in NLK recognition. We investigated whole-mount in situ hybridization (WISH) expression pattern and genomic context of the zebrafish (zf) FAM222B homologues, fam222ba/bb, and fam222aa. Using a double-knockout (dd-KO) fam222ba/bb zf line, we identified aberrant cardiac looping in these larvae and enlarged atrium and ventricle in adult zf. We further tested the c.899G > A variant using human mRNA injections in Tg(kdrl:EGFP) wildtype (wt) reporter-zf, which led to perturbed cardiogenesis. Together, we propose FAM222B as a novel candidate gene for cardiovascular laterality defects.

BACKGROUND: This network meta-analysis aimed to evaluate the predictive value of different blood biomarkers for the prognosis of patients with subarachnoid hemorrhage. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were searched to collect relevant studies published in the last decade. Included studies reported sensitivity or specificity. The quality of included studies was assessed using the QUADAS-2 tool, and network meta-analysis was performed using STATA 18.0. The area under the cumulative ranking curve was calculated to compare the diagnostic efficacy of different biomarkers. RESULTS: A total of 38 studies involving 53 blood biomarkers were included. Among inflammatory markers, cleaved receptors for advanced glycation end-products (cRAGE) (SUCRA: sensitivity 75.9%, specificity 45.4%) showed relatively high predictive efficacy. Among immune cell counts, the fibrinogen and neutrophil-to-lymphocyte ratio (F-NLR) (SUCRA: sensitivity 69.4%, specificity 37.1%) performed particularly well. Among electrolytes and metabolites, maximum sodium concentration (Namax) (SUCRA: sensitivity 80.6%, specificity 18.6%) showed good predictive ability. Cluster analysis indicated that soluble scavenger receptor A (sSRA) among inflammatory markers, the monocyte-to-lymphocyte ratio (MLR) among immune cell counts, and Na⁺ among electrolytes and metabolites have high comprehensive diagnostic value. Subgroup and sensitivity analyses confirmed the robustness of these findings, though results for electrolytes varied across different clinical settings. CONCLUSION: cRAGE, F-NLR, and Na⁺max show relatively high sensitivity or specificity and may be considered as the preferred indicators in future clinical research and practice.

Behçet's disease (BD) is an inflammatory autoimmune disease characterized by relapsing genital ulcers, ocular involvement, and intestinal disorders. Evaluate serum levels of circular RNA (circRNA) FUNDC1 and tumor necrosis factor-alpha (TNF-α) in BD patients and compare them accordingly to healthy individuals. One hundred participants were enrolled in this study and subdivided equally into BD patients and healthy matched individuals. A five mL sample of blood was drawn from each subject and analyzed to measure circRNA-FUNDC1 and TNF-α. Full clinical investigations have been performed, and the Behcet Disease Current-Activity Form score (BDCAF) has been calculated. circRNA-FUNDC1 and TNF-α were measured by quantitative real time PCR and enzyme-linked immunosorbent assay (ELISA) respectively. An up-regulation of circRNA-FUNDC1 as well as TNF-α (p < 0.0001) in BD group were reported compared to controls. Both biomarkers tended to elevate with the activity of the disease as levels were higher in active BD patients than inactive patients. The level of circRNA-FUNDC1 (FC) tended to be higher in patients with negative musculoskeletal and central nervous system (CNS) manifestations than those with positive manifestations (p-values = 0.007, 0.037, respectively). The level of TNF-α was reported higher in those with oral ulcer with (p = 0.041), also in patients with positive skin manifestations than in negative patients (p = 0.025). The level of circRNA-FUNDC1 (FC) was higher in patients who took Azathioprine and steroids (p = 0.019, 0.035) and lower in patients who took cyclosporin (p = 0.049). TNF-α tended to elevate in patients who took Hydroxychloroquine than those who did not (p = 0.040). The upregulated levels of circRNA-FUNDC1 and TNF-α may have a potential role in improving our understanding of the molecular mechanisms underlying BD.

BACKGROUND: Acute unilateral posterior cerebral artery (PCA) infarction involving the hippocampus can cause clinically relevant cognitive impairment, yet the acute neuropsychological syndrome remains insufficiently defined. METHODS: This retrospective observational study included 78 patients with unilateral PCA stroke involving the hippocampus who underwent assessment at a median of 5 days (IQR, 3-7 days) after symptom onset. Thirty-two patients had right-hemispheric and 46 had left-hemispheric infarctions. Cognitive symptoms at onset, structured behavioral observations, standardized clinical tasks, and formal norm-referenced neuropsychological testing were used to characterize impairment across cognitive domains. Group differences were examined, and multivariable logistic regression analyses were performed to identify predictors of cognitive dysfunction. RESULTS: Neuropsychological deficits involved memory, language, attention, executive functions, and visuoconstructive performance, indicating a broad range of cognitive symptoms rather than an isolated amnestic disturbance. Left-hemispheric infarctions were more often associated with amnestic symptoms at onset, and aphasic symptoms occurred exclusively in this group. Compared with right-sided lesions, left-hemispheric infarctions showed higher rates of subjective memory complaints and objective impairment in episodic memory, language production, and comprehension. Formal testing further demonstrated more frequent deficits in naming, categorical word fluency, verbal recall, verbal recognition, and visual recall. In multivariate analyses, lesion side emerged as the main predictor of neuropsychological impairment, whereas additional thalamic ischemia did not significantly improve prediction. DISCUSSION: Acute unilateral PCA infarction involving the hippocampus is associated with multidomain and possibly network-mediated early cognitive dysfunction with more extensive impairment after left-hemispheric lesions independent of thalamic involvement.

Carotid atherosclerosis has been linked to cognitive decline, but evidence regarding its association with domain-specific cognitive performance in understudied non-Western populations remains limited. We investigated the associations of carotid plaque burden and hemodynamic markers with cognitive impairment in 100 community-dwelling Egyptian adults aged ≥ 60 years without prior neurological disease. Carotid plaque burden was quantified by duplex ultrasound using plaque score, and cognition was assessed using the Montreal Cognitive Assessment (MoCA). Sixty-one Participants with a MoCA score ≤ 25 were classified as having possible mild cognitive impairment (MCI). Carotid plaques were detected in 53 participants, and plaque scores were higher in participants with possible MCI (p = 0.035). Internal carotid artery resistive index (ICA RI) was also higher (p = 0.011) among participants with possible MCI. In two separate multivariable models, plaque score (OR 1.41, 95% CI 1.06-1.86; p = 0.020) and ICA RI (OR 1.87, 95% CI 1.01-3.46; p = 0.046) were independently associated with possible MCI. Lower educational attainment showed the strongest association in both models. Plaque burden was most strongly associated with visuospatial and language performance. This cross-sectional study supports further longitudinal studies to determine whether carotid ultrasound markers predict subsequent cognitive decline.

Disruptions in the balance of mitochondrial fission and fusion are implicated in a host of diseases including cardiovascular, metabolic, and neurodegenerative, as well as cancer. Leinheiser et al. proposed a mechanistic model for mitochondrial fission which relies on the oligomerization of Dynamin-related protein 1 (Drp1). In this work, we propose an alternative state-dependent delay-differential equation (sdDDE) framework for mitochondrial fission, which reveals that the intrinsic delay dynamics in Drp1 oligomerization can drive oscillations in the rate of mitochondrial fission. To develop this sdDDE model, we generate a simplified model which disallows oligomer disassembly on the mitochondrial membrane. Following homogenization, the simplified model approaches a steady state dominated by oligomers too small to reach the threshold for fission. Therefore, the fission rate approaches zero when initial conditions reside within the basin of attraction of this fission-free equilibrium. We therefore reincorporate oligomer disassembly on the mitochondrial membrane. However, the attracting, fission-free equilibrium persists. To eliminate this fission-free equilibrium, we incorporate an atomization term into the oligomerization mechanism, highlighting the importance of oligomer disassembly in sustaining mitochondrial fission. Using homogenization techniques, we derive an advection PDE with nonlocal interactions and obtain a reduced sdDDE system governing oligomer partial moments. Analysis of this reduced system reveals an analogous Hopf bifurcation to the Leinheiser et al. fission model, demonstrating that intrinsic delays in Drp1 oligomerization are sufficient to generate oscillatory mitochondrial fission dynamics.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that involves the formation of amyloid-β (Aβ) aggregates, and the development of targeted therapeutic strategies is needed. In the current work, we report the rational design of H102-CP05, a 22-residue chimeric peptide that integrates the β-sheet breaker peptide H102 with the CD63-targeting anchor CP05 to enable extracellular vesicle (EV)-mediated delivery of an Aβ-inhibitory payload. Computational analysis confirmed favorable physicochemical properties and a non-allergenic profile. In silico immunogenicity assessment and C-IMMSIM simulation demonstrated a low risk of anti-drug antibody formation under chronic dosing conditions. Homology modelling and HADDOCK docking (score: -147.2 ± 4.6) predicted a computationally favourable CD63 binding configuration, while 100 ns molecular dynamics simulations confirmed structural stability in both aqueous and EV-mimetic lipid bilayer environments. In vitro cytotoxicity against HEK-293 cells revealed no significant toxicity (10-100 µM). Zebrafish embryo studies indicated acceptable developmental safety at lower concentrations, with concentration-dependent bradycardia observed at higher doses warranting further cardiovascular evaluation. Thioflavin T fluorescence assays demonstrated dose-dependent inhibition of Aβ fibrillation, with near-complete suppression at 100 µM. These findings collectively support H102-CP05 as a promising EV-displayed therapeutic candidate for AD.

BACKGROUND: Bariatric surgery is associated with significant improvements in cardiometabolic health. The apolipoprotein B (ApoB)/apolipoprotein A1 (ApoA1) ratio has been demonstrated to be a strong predictor of cardiovascular disease risk. However, the long-term impact of sleeve gastrectomy (SG) on the ApoB/ApoA1 ratio remains unexplored. METHODS: Observational study including data from a prospective cohort of patients undergoing SG with ApoA1, ApoB, and ApoB/ApoA1 ratio data at baseline, 1 year, and in the long term (3- to 10 years). RESULTS: A total of 376 participants with baseline and 1-year ApoA1, ApoB, and ApoB/ApoA1 were included. For the long-term cohort (3- to 10-year follow-up; mean follow-up, 5.7 ± 2.5 years), 131 participants were included. The ApoB/ApoA1 ratio significantly decreased from baseline to 1 year, 3 to 5 years and >5 years [from 0.68 (95% CI 0.66 - 0.70) to 0.61 (95% CI 0.59 - 0.63), 0.55 (95% CI 0.52 - 0.59), and 0.54 (95% CI 0.51 - 0.58), respectively, adjusted means (95% CI)]. ApoA1 levels significantly increased over time [from 152.47 (95% CI 149.04 - 155.90) to 168.69 (95% CI 164.88 - 172.49), 177.99 (95% CI 171.40 - 184.57), and 184.24 (95% CI 177.46 - 191.02) mg/dL, respectively]. Significant decreases in ApoB levels were observed from baseline to 3-to-5 years [from 100.44 (95% CI 98.92 - 101.97) to 93.53 (95% CI 90.26 - 96.80) mg/dL], but did not persist in the longer term, i.e., > 5 years [97.86 (95% CI 94.53 - 101.19) mg/dL]. CONCLUSION: In a large cohort of participants with obesity, we show that SG leads to significant reductions in the ApoB/ApoA1 ratio in the long term. These findings may provide further insight into changes in the cardiometabolic profile following BS, although further research is needed.

Durable left ventricular assist devices (LVADs) have transformed survival in advanced heart failure, yet driveline infection (DLI) affects 40% of patients by 5 years. The term "Achilles' heel" identifies the driveline as the system's critical vulnerability but does not capture the course of DLI. Achilles died acutely from a heel wound; DLI is chronic, recurrent, treatment-resistant, and progressive. It begins at the exit site, persists through biofilm formation, recurs after apparent remission, progresses along the driveline, and may eventually involve the pump and outflow graft, repeatedly exposing patients to antibiotics, hospitalization and surgery, and ultimately causing death. We therefore propose that DLI be viewed as the "cancer" of LVAD therapy. The analogy is clinical, not biological, and informs treatment: as with cancer, management should be guided by anatomic extent and biological aggressiveness, suppression should not be mistaken for cure, and definitive intervention should precede advanced spread, when source control becomes more difficult. Serial staging and multidisciplinary review are recommended, with hardware removal considered when infection progresses despite suppressive therapy. Potentially curative options for deep DLI include LVAD explantation in patients with sufficient myocardial recovery, transplantation for eligible candidates, and device exchange when transplantation is not feasible. Given the major challenges of treating DLI, every LVAD program must prioritize protocolized prevention from implantation throughout support. Ultimately, curing the cancer of LVAD therapy will require a fully implantable system with no driveline to infect.

Current guidelines recommend complete revascularization for patients with multivessel disease (MVD) presenting with acute myocardial infarction (AMI); however, the optimal timing of complete revascularization remains debated. We aimed to compare the outcomes of immediate versus staged complete revascularization in this population. Following PRISMA and Cochrane methodological standards, we systematically searched electronic databases from inception to March 2026 to identify randomized controlled trials (RCTs) comparing immediate versus staged complete revascularization in AMI patients with MVD. The primary outcomes were major adverse cardiac events (MACE) and all-cause mortality, assessed using reconstructed individual patient data (IPD) derived from published Kaplan-Meier curves. Secondary outcomes included cardiovascular disease (CVD) mortality and unplanned repeat revascularization. Hazard ratios (HRs) were pooled using random-effects Cox regression models. Thirteen RCTs including 8,247 patients (3,855 [46.7%] immediate complete revascularization; 4,392 [53.3%] staged complete revascularization) were analyzed. There were no significant differences between strategies in the risks of MACE (HR, 0.88; 95% CI, 0.76-1.01; p = 0.08), all-cause mortality (HR, 1.30; 95% CI, 0.91-1.86; p = 0.10), or CVD mortality (HR, 1.64; 95% CI, 0.96-2.78; p = 0.07). Immediate complete revascularization complete revascularization was associated with a significantly lower 4-year risk of unplanned repeat revascularization (HR, 0.44; 95% CI, 0.30-0.64; p < 0.001). In patients with AMI and multivessel disease, immediate and staged complete revascularization yielded similar overall estimates for MACE and mortality, although clinically meaningful differences, particularly for mortality, cannot be excluded. Immediate complete revascularization significantly reduced the risk of repeat revascularization.

The Popeye domain-containing protein 1 (Popdc1, also known as Bves) is a transmembrane protein whose dysfunction is closely associated with various diseases. Clinical studies have identified that mutations in the bves gene predispose individuals to limb-girdle muscular dystrophy. However, a marked reduction in Bves protein expression has been observed in patients with heart failure, highlighting a critical unresolved challenge in understanding its role in disease pathogenesis. In this study, we discovered that bves deficiency drives cardiac contractile dysfunction, thereby revealing a novel mechanism underlying heart failure pathogenesis. The study found that bves knockout led to cardiac contractile dysfunction in zebrafish during both embryonic and adult stages, with a significant reduction in ejection fraction. Twelve-month-old bves knockout zebrafish exhibited ventricular dilation, increased cardiomyocyte size but significantly decreased cell numbers, and aggravated fibrosis of atrioventricular valves. Transmission electron microscopy revealed widened Z-lines and shortened I-bands in myocardial fibers of the bves knockout group. Collectively, these findings provide compelling evidence that bves knockout induces heart damage. Transcriptome analysis showed disrupted expression of ATP synthesis-related genes and activation of the mitochondrial autophagy pathway following bves knockout. In bves knockout zebrafish, myocardial mitochondria exhibited abnormal structure and impaired oxidative respiratory function, with upregulated expression levels of a series of protein complexes in the mitochondrial electron transport chain. These studies have for the first time established that myocardial mitochondrial structural/functional damage caused by bves deficiency may be associated with the pathogenesis of heart failure, providing a new perspective for the occurrence and development of heart failure.

PURPOSE: The management of thymoma patients with pleural dissemination remains challenging. We conducted a prospective phase 2 study to investigate the safety and efficacy of surgery followed by entire hemithoracic radiotherapy (EHRT) in these patients. MATERIALS AND METHODS: Thymoma patients with pleural dissemination (de novo or recurrent) were enrolled. After macroscopic resection, intensity-modulated radiotherapy (IMRT) of 14 Gy in 14 fractions was delivered to the entire hemithorax. An additional dose of 30 Gy in 15 fractions was delivered to the mediastinal tumor bed if the stage of the primary tumor was higher than T2. RESULTS: Between April 2020 and December 2021, 71 patients completed the study protocol. There were 30 male and 41 female patients, with a median age of 46 years (range, 26-75). There were 32 de novo cases and 39 recurrent cases. During a median follow-up of 57 months, two patients (2.8%) died: one from disease progression and the other from heart disease. A total of 34 patients (47.9%) developed disease progression, including pleural recurrence inside the radiation field (n=24) and outside the field (n=10). The median progression-free survival (PFS) was 50 months (95% CI, 45.95-54.39). The 3-year and 5-year PFS were 68.9% (95% CI, 56.7%-78.3%) and 50.8% (95% CI, 38%-62.3%), respectively. The 3- and 5-year recurrence-free survival rates (defined as no relapse inside the radiation field) were 78.8% (95% CI, 67.4%-86.7%) and 66.5% (95% CI, 53.3%-76.7%), respectively. The 5-year overall survival (OS) was 98.6%. Nausea, fatigue, and vomiting were the most frequent toxicities, and most were mild in severity. CONCLUSIONS: Surgical resection followed by EHRT is a safe treatment approach for thymoma patients with pleural dissemination, yielding promising local control. The optimal dose and target volume of radiotherapy warrant further investigation.