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Lipoprotein(a) [Lp(a)] is a potent, independent causal risk factor for coronary artery disease (CAD). This study aimed to assess the association between Lp(a) and the diagnosis, clinical presentation, and angiographic characteristics of obstructive CAD and occurrence of myocardial infarction (MI). We included 446 individuals with very high Lp(a) (>230 nmol/L) who underwent routine lipid profiling, matched 2:1 by age and sex using nearest-neighbor propensity matching to 223 controls with low Lp(a) (≤7 nmol/L). Kaplan-Meier analysis was used to assess CAD- and MI-free survival. Multivariable ORs were calculated for multivessel disease and the SYNergy Between percutaneous coronary intervention with TAXus and Cardiac Surgery-1 score. Median follow-up time, defined by age at last follow-up, was 60 years (Q1-Q3: 50-71). Individuals with very high Lp(a) had significantly lower event-free survival time for the diagnosis of obstructive CAD and occurrence of MI (P = 0.006 and P = 0.012, respectively). In multivariable analysis, Lp(a) was associated with multivessel CAD (adjusted OR: 1.43 [per 100 nmol/L]; 95% CI: 1.04-1.96; P = 0.028), but not with an intermediate or high SYNergy Between percutaneous coronary intervention with TAXus and Cardiac Surgery-1 score (adjusted OR: 1.28 [per 100 nmol/L]; 95% CI: 0.82-1.99, P = 0.279). Individuals with very high Lp(a) levels had a 2.4-fold higher risk of ST-segment elevation MI and a 15.9-fold higher risk of recurrent MI compared to those with low Lp(a). Very high Lp(a) is associated with earlier diagnosis of obstructive CAD and MI, predominantly ST-segment elevation MI. In addition, individuals with very high Lp(a) levels seem at a particular high risk of recurrent MI. Show less

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS), with plasma levels largely unaffected by lifestyle modification or conventional lipid-lowering therapy. Although international guidelines increasingly recognize Lp(a) as a risk-enhancing factor, in many Asian populations thresholds for high Lp(a) and treatment strategies remain undefined. This Korean position paper, developed by the Lp(a) Task Force of the Korean Society of Lipid and Atherosclerosis, presents an evidence-based summary of the pathophysiology, clinical relevance, and therapeutic landscape surrounding Lp(a), with a focus on Korean-specific data. It reviews the genetic architecture of Lp(a), ethnic variability in concentrations, and its mechanistic roles in inflammation, thrombosis, and calcification. Based on large Korean cohorts, a 3-tiered classification is proposed of normal (<30 mg/dL), borderline high (30-49 mg/dL), and high (≥50 mg/dL), harmonizing global thresholds with local data. The document also highlights the limitations of current Lp(a) assays in Korea, and calls for standardized, isoform-insensitive testing. Novel therapeutics, including antisense oligonucleotides, small interfering RNAs, and small molecular inhibitors, have shown promising Lp(a)-lowering effects, with multiple phase 3 trials currently ongoing, or in planning. Given the unmet clinical need, the paper recommends incorporating Lp(a) into cardiovascular risk assessment, and calls for Korean-specific longitudinal studies, national screening strategies, and participation in clinical trials. These efforts will help clarify Lp(a)-associated risk in Korean patients and guide the adoption of future targeted therapies. Show less

DNA double-strand break repair has emerged as a vital pathway to repair DNA damage seriously related to the risk of colorectal cancer (CRC). To explore valid susceptible biomarkers of CRC via investigating the association of single nucleotide polymorphisms in DSBR genes with CRC risk, seven polymorphisms located in 3'-untranslated regions of DSBR genes including RAD51 rs11852786, RAD51B rs963917, BRCA1 rs12516 and rs8176318, BRCA2 rs15869, XRCC4 rs2035990 and XRCC5 rs2440 were detected and analyzed in a CRC case-control study (cases (202) and also controls (202)). The PolymiRTs and miRSNP database were used to predict the microRNAs that can bind to 3'UTR SNPs. Since long non-coding RNA as a miRNA "sponge" played the role of competing endogenous RNA, DAVID database was used to find the lncRNAs that can bind to the candidate miRNA seed sequences. BRCA1 rs12516 minor A allele was found to be linked with a higher risk of CRC than its major G allele (OR = 2.716, 95%CI: 1.394-5.292, P = 0.003). The stratified analyses demonstrated rs12516 AA genotype with a more elevated risk of CRC in male (OR = 3.089, 95% CI:1.315 ~ 7.255) or age > 50 population (OR = 3.318, 95%CI:1.571 ~ 7.006) than its GG genotype. BRCA1 rs12516 A allele created a novel miR-4704-5p binding target, and there was a negative correlation between miR-4704-5p and BRCA1 expression (r =-0.7199, P = 0.0440). Based on the theory of ceRNA network, it was predicted that lncRNA BDNF-AS can competitively bind to miR-4704-5p, whose expression was exhibited to be negatively correlated with BDNF-AS (r=-0.3481, P = 0.0375). On the contrary, BDNF-AS expression showed a positive correlation with BRCA1 mRNA level in colorectal tissue carrying rs12516 of A allele (adjacent tissue: r = 0.7269, P = 0.0411; cancer tissue: r = 0.7134, P = 0.0469). ROC curve showed both BDNF-AS (AUC = 0.651, P = 0.0277) and miR-4704-5p (AUC = 0.7215, P = 0.0012) can distinguish CRC tissues from their adjacent tissues. BRCA1 rs12516 is characterized as a potential biomarker associated with CRC risk, via a possible functional ceRNA network of BDNF-AS, miR-4704-5p and BRCA1. The interaction of a lower expression of BDNF-AS, a higher expression of miR-4704-5p and rs12516 A allele could together increase the risk of colorectal cancer. Show less

Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD), yet its underlying mechanisms remain poorly understood. Apolipoprotein E4 (APOE4), a genetic risk factor of Alzheimer's Disease, has been associated with PD-related cognitive impairment. However, findings are inconsistent, highlighting the need for further investigation. Neuroimaging studies have found gray matter abnormalities, mainly reductions in gray matter volume (GMV) and cortical thickness (CTh), in both cognitively impaired PD patients and APOE4 carriers. Yet, APOE4's role in these structural changes and their cognitive impact in PD is underexplored. This study aimed to determine whether APOE4 influences early structural brain differences in terms of GMV and CTh in PD prior to the emergence of cognitive dysfunction. A total of 51 PD APOE4 carriers and 120 non-carriers who were cognitively unimpaired from the Parkinson's Progression Markers Initiative (PPMI) database were included. T1-weighted MRI scans were used to calculate GMV and CTh in regions previously associated with PD-related cognitive impairment, including hippocampal subregions. Cognitive scores assessing global cognition and specific cognitive domains were used to examine associations between regions showing significant GMV or CTh group differences and cognitive performance. PD APOE4 carriers showed increased GMV in the left angular gyrus (AnG) and decreased GMV in the left nucleus accumbens (NAcc) compared to non-carriers, though neither survived multiple comparison correction. Left AnG GMV correlated with visuospatial function in both groups but did not remain significant after co-variate adjustment. Left NAcc GMV correlated with visuospatial function and working memory, but only in non-carriers even after co-variate adjustment. No group differences were observed in CTh measures and hippocampal subregion GMVs. This study suggests that APOE4 may not influence cognitive function in PD by affecting GMV and CTh. However, longitudinal analyses must confirm these observations. Show less

Neurodegenerative diseases, which pose significant challenges for effective treatment, often involve risk variants of lysosomal gene products that disrupt lysosomal function, leading to the accumulation of indigestible materials and damage to brain cells. The lysosome is a degradative organelle and a signaling hub that senses nutrient availability. How lysosomal dysfunction contributes to neurodegenerative diseases is an important open question. In this study, we identified CLN3 (ceroid lipofuscinosis, neuronal 3), an endolysosomal protein that is linked to Batten disease, as an evolutionarily conserved protein that facilitates lysosomal chloride efflux. Additionally, we report that a natural compound with anti-inflammatory properties-the curcumin analog C1, which is a TFEB (transcription factor EB) activator-could enhance CLN3 activity and improve lysosomal function. These findings provide new insight into the role of CLN3 in lysosomal ion homeostasis and raise the possibility that modulation of the TFEB-CLN3 signaling axis may hold therapeutic potential for lysosomal storage disorders. Show less

The gastrointestinal system is of particular importance in radiation biodosimetry because of its constant cell renewal and sensitivity to radiation-induced injury. It has been reported that total abdominal irradiation causes distant cognitive defects in a mouse model. In this study, we demonstrated that metformin alleviated the cognitive dysfunction caused by total abdominal irradiation. No neuropathological changes were observed in hippocampal tissues in control, irradiated, and irradiated plus metformin-treated groups. However, we found that metformin treatment improved the expression of brain-derived neurotrophic factor and the phosphorylation level of cAMP response element-binding in the hippocampus from irradiated mice. Furthermore, our results revealed that metformin treatment reduced the expression of miR-34a-5p, which targets the brain-derived neurotrophic factor mRNA, in the small intestine, peripheral blood, and hippocampus. More importantly, injection of miR-34a-5p agomir inhibited the enhancement effects of metformin on the cognitive defects induced by total abdominal irradiation, as well as the enhanced expression of BNDF and the phosphorylation level of cAMP response element-binding in the hippocampus. Thus, our results provide alternative strategies for the treatment of total abdominal irradiation-induced distant cognitive impairment using metformin and further confirmed that miR-34a-5p is a potential drug target to reduce the cognitive defects caused by total abdominal irradiation. Show less

Repetitive traumatic brain injury (RTBI) refers to brain injuries resulting from an external mechanical force causing cumulative and frequently severe neurological consequences. This study aimed to explore the neuroprotective effect of alogliptin (ALO) on RTBI-provoked endoplasmic reticulum (ER) stress and investigate the potential underlying mechanisms. For RTBI induction, rats were exposed to a sharp-edged weight at the right interior frontal area of the right cortex, one drop per day for five successive days. ALO (20 mg/kg/day, p.o.) was administered for one week. Results depicted that ALO recovered motor abnormalities and enhanced motor coordination in the open field test, decreased immobility and increased climbing time in the forced swimming test, and corrected histological aberrations. Moreover, ALO counteracted RTBI-triggered ER stress via suppression of activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), aggregation of β-amyloid and Tau proteins, as well as elevation of the cortical content of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrKB). ALO also exhibited an antioxidant and anti-inflammatory potential in addition to its effect on the gene expression of miRNAs (miRNA-322 and miRNA-125b). In conclusion, ALO exhibited a neuroprotective effect by mitigating ER stress induced in an RTBI rat model. Show less

COG133, an apolipoprotein E-derived mimetic peptide, has been proposed as a therapeutic candidate due to its immunomodulatory properties. Its potential role in diabetic wound healing, where impaired fibroblast function and chronic inflammation are major obstacles, remains largely unexplored. In this study, human diabetic dermal fibroblasts were treated with COG133 to evaluate its effects on cell viability, migration, and gene expression of ApoE, miR-146a, NF-κB, TRAF-6, and IL-6. In addition, the antibacterial and antibiofilm activities of COG133 were assessed against Gram-positive and Gram-negative bacteria. COG133 enhanced fibroblast migration without affecting viability, upregulated miR-146a, and reduced IL-6 and ApoE expression, while NF-κB and TRAF-6 remained unchanged. Antibacterial assays revealed inhibitory effects, with the lowest MIC against Show less

Systemic inflammation has been identified as a key factor in neurodegeneration but the value of circulating inflammatory proteins in dementia risk prediction and their causal role has not been elucidated. We leveraged proteomic data from 43,685 UK Biobank participants to investigate associations between 728 Olink inflammatory proteins and incident dementia using Cox proportional-hazards (Cox-PH) models. We used Cox-PH with LASSO regularisation to calculate a sparse signature of inflammatory proteins (ProSig) predicting incident dementia. Linear regressions assessed the association between ProSig and individual proteins with brain image-derived phenotypes and Brain Age in participants with available neuroimaging data (n = 4,106). Formal mediation analyses investigated whether inflammatory proteins mediated associations between genetic and modifiable risk factors and dementia outcomes. Mendelian randomisation (MR) tested the causal relationship between inflammatory proteins and dementia outcomes. 218 inflammatory proteins were individually associated with incident dementia in Cox-PH models (p By triangulating evidence, this study shows that inflammatory proteins improve dementia risk prediction and play heterogeneous roles in dementia pathophysiology. Show less

Brain-derived neurotrophic factor (BDNF) has been suggested to support dopaminergic neuron's endurance and dopamine release. Its Val66Met polymorphism might modify Parkinson's disease (PD) evolution, although evidence in Asian populations remains limited. This study aimed to explore how the BDNF rs6265 genotypes are associated with the clinical characteristics and longitudinal progression patterns of PD patients in a Korean population. A total of 247 patients were enrolled and followed for a mean duration of 50.9 ± 23.9 months. Baseline and/or periodic assessments captured motor severity, non-motor burden, cognition, orthostatic stress, cardiac denervation, and presynaptic dopamine transporter availability. The repeated measures were manipulated to infer any genotypic differences in the trajectories of each clinical domain. Genotype frequencies were 31.2% (77/247) for Val/Val and 68.8% (170/247) for Met-allele carriers. Baseline clinical characteristics and presynaptic dopamine transporter availability were comparable between genotypes; however, Val homozygotes showed more preserved myocardial innervation and poorer non-frontal cognitive performance. Longitudinal analyses demonstrated genotype-specific increases in motor and cognitive severity. Compared to Met-allele carriers, the homozygous Val group exhibited accelerated motor progression and more rapid decline in frontal domain after three years of follow-up. The differences in myocardial denervation at diagnosis, cognitive profiles, and motor progression might suggest a potential modulatory role of BDNF polymorphism in PD progression in the Korean population. Show less

Transferrin receptor 1 (TfR1), an intracellular iron receptor, has multiple biological functions. We have previously reported that aortic TfR1 expression increases in human and murine abdominal aortic aneurysm, but its role in the development of atherosclerosis remains unclear. In the present study, we generated apolipoprotein-E (ApoE) and TfR1 deficient mice and examined the impact of its deletion on the development of atherosclerosis. Homozygous ApoE deficient ( These results indicate that TfR1 deletion attenuates the development of atherosclerotic lesion formation in Show less

Alzheimer's disease is characterized by intertwined pathologies including neuroinflammation, driven by microglial dysfunction, and metabolic disturbances such as lipid dyshomeostasis. Mesenchymal stem cell-derived exosomes (MSC-Exos) hold therapeutic promise, Still, it is unknown whether they can simultaneously address these co-occurring impairments via specific molecular cargos, such as long non-coding RNAs (lncRNAs). Transcriptome sequencing of exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) revealed high expression of the long noncoding RNA ENST00000629969 (hereinafter referred to as lncRNA-9969). We isolated exosomes from hUC-MSCs (WT-Exo) and established human umbilical cord blood mesenchymal stem cells stably knocked down for lncRNA-9969 via siRNA, from which corresponding exosomes (KD-Exo) were isolated. Cross-species analysis identified the mouse homolog of lncRNA-9969 as ENSMUST00000200021 (hereinafter referred to as lncRNA-0021). Cellular experiments employed an Aβ₂₅₋₃₅-induced SH-SY5Y cell model to evaluate the protective effects of exosomes. In animal experiments, 6-month-old APP/PS1 mice received biweekly tail vein injections of WT-Exo or KD-Exo for 4 weeks. Phenotypic and mechanistic analyses were subsequently conducted using the Morris water maze, Western blot, immunofluorescence, qPCR, and transmission electron microscopy. In Aβ-injured SH-SY5Y cells, WT-Exo significantly attenuated cellular damage and promoted Aβ clearance, whereas the protective effect of KD-Exo was markedly reduced. In APP/PS1 mice, WT-Exo treatment significantly improved spatial memory deficits and upregulated hippocampal expression of synaptic proteins synaptophysin (Syn) and brain-derived neurotrophic factor (BDNF). Molecular mechanism studies demonstrated that lncRNA-0021 directly binds mmu-miR-6361. Through this ceRNA mechanism, exosome-delivered lncRNA activated the mTOR/p70S6K autophagy pathway, regulated lipid metabolism-related genes, promoted microglial polarization toward the protective M2 phenotype, and suppressed pyroptosis. These beneficial changes were not observed in the KD-Exo-treated group. hUC-MSC-derived exosomes exert neuroprotective effects by delivering functional lncRNA-9969. Its highly conserved homolog in mice, lncRNA-0021, achieves coordinated multi-target regulation of neuroinflammation, pyroptosis, and metabolic disturbances by sequestering miR-6361 and activating downstream signaling pathways. This study elucidates the central role of exosomal lncRNAs in AD pathology and provides new insights for developing RNA-based multi-target therapeutic strategies. Show less

Overactivation of hepatic de novo lipogenesis (DNL) contributes to fatty liver disease. Although glucose and fructose strongly promote DNL, diary-rich galactose is only weakly lipogenic. However, whether and how it regulates hepatic DNL remains unclear. In this study, we investigated whether low-dose galactose supplementation attenuates glucose- or fructose-induced DNL activation and protects against fatty liver diseases driven by DNL overactivation, such as alcohol-associated liver disease (ALD). In this study, we used integrated hepatocyte and mouse models to assess hepatic DNL and related signaling under high-glucose or high-fructose conditions, with or without low-dose galactose. Pharmacological and genetic interventions targeting the Leloir and hexosamine biosynthetic pathways (HBP) defined underlying mechanisms. For in vivo validation, male C57BL/6 mice were fed an isocaloric control or ethanol-containing diet for 4 wk. We found that glucose engages the HBP-mTORC1-SREBP-1c axis to stimulate hepatic DNL, whereas fructose acts predominantly through carbohydrate-responsive element-binding protein (ChREBP). Low-dose galactose selectively suppressed glucose-induced hepatic fat accumulation, concomitant with the inhibition of the HBP-mTORC1-SERBP-1c pathway. These effects required an intact Leloir pathway for galactose metabolism and were not observed with fructose. In alcohol-fed mice, hepatic HBP-mTORC1-SREBP-1c signaling was markedly upregulated, contributing to steatosis and liver injury. Replacing even a small fraction of dietary glucose with galactose normalized these alterations, attenuating hepatic lipid accumulation and injury without altering systemic glucose levels. In conclusion, glucose-induced hepatic lipogenesis involves the HBP-mTORC1-SREBP-1c pathway, which is also activated during chronic alcohol exposure. Low-dose galactose, obtainable from dairy sources, attenuates this pathway, thereby limiting excessive lipogenesis and protecting against early-stage ALD. Show less

Cerebral deposition of fibrillar amyloid-β (Aβ) is a pathological hallmark of Alzheimer's disease. Although Aβ is present in human placentas and accumulates in preeclamptic placentas characterized by poor placentation, the production and role of Aβ in the human placenta remain unclear. Because hypoxia in mid-to-late pregnancy is a risk for preeclampsia, we found that levels of hypoxia-inducible factor 1-α and β-secretase (BACE-1) increased concurrently with placental Aβ deposition in late-stage preeclamptic placentas. We also found that a human cytotrophoblast (CTB) model, BeWo cells, actually produced Aβ species and that hypoxia increased Aβ production and BACE-1 protein levels. Aβ42 fibrils inhibited CTB syncytialization, a critical step in maintaining pregnancy, by inducing loss of membrane localization of cell-cell adhesion molecules. Primary human CTBs confirmed these observations. Taken together, our results suggest that increased Aβ production in CTBs by hypoxia may lead to the formation of Aβ fibrils, which inhibit syncytiotrophoblast formation and are detrimental to pregnancy. Thus, our results reveal the novel role of Aβ fibrils in the pathogenesis of preeclampsia. Show less

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive impairment and the accumulation of amyloid-β (Aβ) peptides. In this study, a novel series of triazole and phosphazine derivatives were synthesized and evaluated for neuroprotective activity in an aluminum chloride (AlCl Show less

Astrocyte-derived extracellular vesicles (ADEVs) have emerged as a novel research tool in the field of central nervous system disorders. However, significant differences in yield and purity exist among extracellular vesicles (EVs) isolated by different methods, leading to considerable heterogeneity in clinical study outcomes. Therefore, establishing appropriate normalization strategies to enhance comparability across results is a key prerequisite for their clinical translation. This study included 15 patients with major depressive disorder (MDD) and 15 healthy controls (HCs). ADEVs were isolated from plasma using ultracentrifugation combined with immunoaffinity capture. Subsequently, the levels of brain-derived neurotrophic factor (BDNF), five EV biomarkers (CD9, CD63, CD81, Alix, and TSG101), and particle counts in ADEVs were quantified. In addition, plasma lipoprotein levels were measured. Our results demonstrated a lack of significant correlation between particle counts and the levels of five EV biomarkers in plasma ADEVs, whereas strong correlations were observed among the five biomarkers themselves. Normalization of BDNF levels to CD81 or CD9 revealed a significant decrease in the MDD group, whereas normalization to EV particle counts or other EV biomarkers did not show such differences. Notably, plasma levels of apolipoprotein B (APOB), low-density lipoprotein (LDL), and total cholesterol (TC) significantly interfered with the measurement of particle counts. In summary, under conventional EV isolation and detection conditions, our findings support the use of EV biomarker levels rather than particle counts as a normalization method for quantifying target proteins of ADEVs in plasma. [Image: see text] The online version contains supplementary material available at 10.1186/s12888-026-07796-6. Show less

Autophagy is integral to the rapid proliferation of esophageal squamous cell carcinoma (ESCC), and its regulation presents a promising avenue for therapeutic intervention. Recent studies have elucidated the interplay between autophagy and glucose metabolism, while there is a paucity of anticancer drugs that concurrently target these 2 biological processes. In this study, we identified a natural compound, Show less

Factors underlying discordant visual and quantitative amyloid beta-positron emission tomography (Aβ-PET) results and their clinical implications are not well understood. Participants from the 1Florida Alzheimer's Disease Research Center (1FLADRC) underwent Aβ-PET, blood draw, brain magnetic resonance imaging (MRI), and neuropsychological testing. We evaluated differences in demographics, apolipoprotein E ( We studied 386 participants (mean age ± SD: 70.7 ± 7.8, 55.2% female, 44.6% Hispanic White). Compared to V+/Q-, V-/Q+ had a higher frequency of Discordant Aβ-PET findings likely hold clinical significance and may reflect early stages of neuropathological progression. Groups with concordant/discordant visual-quantitative amyloid beta-positron emission tomography (Aβ-PET) results were compared.Visual-/quant+ were more likely than visual+/quant- to be apolipoprotein E ( Show less

Residual cardiovascular risk persists in type 2 diabetes mellitus (T2DM) despite intensive risk-factor management. Apolipoprotein B (apoB) and excess apoB are potentially promising biomarkers for identifying residual cardiovascular risk. We assessed apoB and excess apoB in T2DM for incremental prediction of atherosclerotic cardiovascular disease (ASCVD) risk. This prospective cohort included 11,918 UK Biobank participants (mean age 59.7 ± 6.6 years; 61% male) with T2DM and no ASCVD at baseline. Excess apoB was defined as the observed minus predicted apoB, where the predicted value was derived using a linear regression model of apoB on low-density lipoprotein cholesterol (LDL-C) fitted in a statin-naïve reference subset with triglycerides ≤ 1.0 mmol/L. The primary endpoint was incident ASCVD. Secondary endpoints included major adverse cardiovascular events (MACE) and all-cause mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox models. Nonlinearity was assessed using restricted cubic splines. Incremental improvements were quantified using the C-index, net reclassification improvement (NRI). During a median 185.3-month follow-up, 2,548 ASCVD and 1,205 MACE events occurred. ApoB was linearly related to ASCVD and MACE, while excess apoB showed J-shaped associations with a nadir near - 7.5 mg/dL for ASCVD. Both apoB and excess apoB showed positive associations with ASCVD across ascending percentile categories. Versus < 50th percentile, HRs (95% CIs) for ASCVD in higher apoB categories (50-<75th, 75-<90th, ≥ 90th) were 1.31 (1.16-1.49), 1.51 (1.25-1.81), and 1.47 (1.10-1.95); corresponding HRs (95% CIs) for excess apoB were 1.50 (1.36-1.66), 1.45 (1.29-1.63), and 1.53 (1.33-1.76), respectively. Similar but weaker risk gradients were observed for MACE. Neither apoB nor excess apoB was associated with all-cause mortality. Excess apoB yielded greater prediction improvement than apoB (ΔC-index: 0.009 vs. 0.002; NRI: 0.270 vs. 0.101) and better stratified risk in statin users and those with LDL-C ≤ 100 mg/dL (P for interaction < 0.05). In T2DM, apoB is independently associated with ASCVD but adds limited discrimination over conventional lipids. Excess apoB yielded improved discrimination and reclassification, and may serve as a complementary ASCVD risk marker, particularly in statin-treated settings. However, its clinical application requires external validation and standardization. Show less

Current treatment strategies for glaucoma, the leading cause of irreversible blindness, only target intraocular pressure (IOP) but not the underlying retinal ganglion cell degeneration. IOP management is not always effective, necessitating neuroprotective strategies. Lysophosphatidic acid (LPA) is an extracellular signaling molecule implicated in modulating inflammation. It exerts its signaling effects through its receptors (LPAR1-6). Here we test the efficacy of PIPE-791, an LPAR1-selective antagonist, in conferring neuroprotection and modulating neuroinflammation in glaucoma. A bead-induced rat ocular hypertension (OHT) model of glaucoma was used to test PIPE-791 (administered intraperitoneally at 3 mg/kg dosing). We monitored IOP through tonometry and evaluated PIPE-791's neuroprotective capacity by studying retinal ganglion cell survival using cell counting and its effects on retinal vasculature, immune cell numbers and cytokine profile. PIPE-791 had no effect on IOP in normotensive (NT) or OHT rat eyes. It also did not have any neuroprotective effect on retinal ganglion cell survival, nor did it normalize the changes in retinal vasculature observed in OHT retinas. Although PIPE-791 treatment increased microglial numbers in NT retinas, there was no effect in OHT retinas. Cytokine array profiling also revealed no significant effects for PIPE-791 on the cytokine changes between the NT and OHT retinas. These lack of changes could potentially be explained by the fact that LPAR1 protein levels are decreased in OHT retinas. Our data suggests that targeting LPAR1 through pharmacological means does not provide neuroprotection or modulate neuroinflammation favorably in glaucoma. Our study provides evidence that pharmacological targeting of LPAR1 as a potential therapeutic avenue in glaucoma may not be beneficial. Show less

Sex differences in the association between vascular factors and cognitive outcomes remain unclear. We aimed to investigate the associations of blood pressure metrics (hypertension, systolic blood pressure [SBP), pulse pressure, ankle and brachial pressures, and ankle to brachial pressure index [ABI]) with the risk of cognitive decline and dementia. We conducted a population-based longitudinal analysis using data from the Atherosclerosis Risk in Communities (ARIC) study (begun in 1987-1989) in the United States. We analyzed a total of 12,268 participants aged 45-64 years who had validated exposure measurements, cognitive function tests (first administrated 1990-1992), and followed up for incidence of dementia through December 2019. Cognitive function was assessed using the Digit Symbol Substitution Test, the Delayed Word Recall Test, and the Word Fluency Test. Dementia cases were identified through a standardized clinical evaluation process, mostly adjudicated by expert reviewers. We performed sex-stratified analyses to examine the associations of blood pressure metrics and APOE ε4 allele with the risk of cognitive decline and dementia. Over a median follow-up of 26.4 years, 2698 participants developed dementia. Women aged 55-64 had a significantly higher incidence of dementia than men aged 55-64 (14.8 vs. 11.8 per 1000 person-years; p < These findings highlight notable sex differences in the association between vascular factors and cognitive decline and dementia risk. Women appear more vulnerable to both genetic and vascular risk factors, emphasizing the need for sex-specific approaches in research, prevention, and intervention strategies for cognitive impairment. NIH. Show less

Postinfectious olfactory dysfunction (PIOD) is common in COVID-19 patients. This 2-arm double-blinded randomized controlled trial (RCT) aimed to establish proof-of-concept for vitamin A versus placebo as a treatment modality for patients with PIOD. This study compared 9,000 IU daily self-administered vitamin A intranasal drops versus peanut oil drops over 12 wk in COVID-19 patients with PIOD. Outcome measures included: olfactory bulb volume (OBV), olfactory sulcus depth, cerebral functional MRI blood oxygen level dependent (BOLD) signal, Sniffin' Sticks TDI score, SSParoT, olfactory disorder questionnaire (ODQ) score, and brain-derived neurotropic factor (BDNF) levels were collected from participants at baseline and after trial intervention at 12 wk. Fifty-seven PIOD were recruited in the trial and allocated to vitamin A or placebo arm at a 2:1 ratio. After withdrawals and exclusions, 30 participants in the vitamin A arm and 15 in the placebo arm were analyzed. There was no significant difference in the change in OBV between both groups. Aside from an improvement in the quality-of-life component of ODQ questionnaire scores (P = 0.01), there were no significant differences in any of the other secondary outcome measures. This proof-of-concept trial has demonstrated no significant effect of intranasal vitamin A on olfactory function in COVID-19 PIOD patients. Further work is required to identify other therapeutic agents in the management of PIOD or evaluate a different PIOD cohort with non-COVID etiology. Show less

Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Gene Fusions (MLN-eo-TK) represent a distinct and heterogeneous group of hematologic malignancies characterized by recurrent gene fusions involving tyrosine kinases, such as PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, ETV::ABL1 and other partner genes/variants. Among these, gene rearrangements involving PCM1::JAK2 are rare and may present diagnostic challenges, particularly when manifesting as acute lymphoblastic leukemia (ALL). We describe a case of a patient who presented with B-cell acute lymphoblastic leukemia (B-ALL) with a JAK2 rearrangement. After the induction therapy, strong myeloid proliferation in bone marrow without evidence of residual lymphoblasts was observed and JAK2 rearrangement was recognized to be a consequence of translocation t(8;9)(p22;p24)] resulting in PCM1::JAK2 fusion. This finding indicated the presence of an underlying chronic myeloid/lymphoid neoplasm, meeting criteria for MLN-eo-TK. Following an inadequate response to standard chemotherapy, salvage regimens incorporating targeted agents (JAK2 and BCL-2 inhibitors) and allogeneic bone marrow transplantation were administered, all of which unfortunately resulted in short-lived clinical benefit. The case highlights the importance of distinguishing de novo lymphoid malignancies from MLN-eo-TK, especially when JAK2 rearrangements are detected. Recognition of the clonal myeloid component during or after lymphoid-directed therapy has important diagnostic and therapeutic implications, supporting the use of targeted JAK2 inhibition in addition to standard chemotherapy. Show less

Parenting behaviors, including autonomy support and psychological control, have been shown to significantly influence adolescent non-suicidal self-injury (NSSI). However, the underlying mechanisms linking heterogeneous parenting behavior profiles to adolescent NSSI remain unclear. This two-wave longitudinal study (with a one-year interval) of 742 Chinese adolescents (52.7% girls; Mage at Time 1 = 13.40 years) identified four distinct parenting profiles using latent profile analysis (LPA): Supportive (43.6% of the sample), Controlling (17.4%), Moderate Mixed Parenting (33.1%) and High Mixed Parenting (5.9%). Multicategorical serial mediation analysis revealed that adolescent emotion regulation difficulties and depressive symptoms serially mediated the relationship between parenting profiles and NSSI for adolescents in the Controlling, Moderate Mixed Parenting and High Mixed Parenting Profiles. Notably, these mediating effects were significant only for girls. These findings underscore the importance of adopting person-centered and sex-sensitive intervention strategies to mitigate the adverse effects of detrimental parenting behaviors on adolescent NSSI. Show less

The comparative efficacy and safety profiles of PCSK9 inhibitors in familial hypercholesterolemia (FH), including genotype-dependent treatment responses, remain unclear. This systematic review was conducted in accordance with the Preferred Reporting Items for Meta-Analyses guidelines. A network meta-analysis of randomized clinical trials evaluating the use of PCSK9 inhibitors for the treatment of FH patients, including subgroup analyses of efficacy, was performed. Fifteen randomized clinical trials (n = 2954 patients) were included. All PCSK9 inhibitors significantly improved lipid parameters compared to control. In heterozygous FH (HeFH) populations, ongericimab showed the greatest reductions in LDL-C (mean difference [MD]: -74.98 %), ApoB (MD: -64.64 %), and Lp(a) (MD: -59.66 %), with SUCRA rankings of 68.7 %, 63.6 %, and 95.0 %, respectively. However, these results are based on a single trial and require further validation. No significant lipid-lowering effects were observed in HoFH patients. In terms of safety, lerodalcibep showed the most favorable profile for injection-site reactions and ALT >3 × ULN, with SUCRA values of 98.5 % and 96.7 %, respectively. Inclisiran was associated with a significantly higher risk of injection-site reactions. PCSK9 inhibitors generally show favorable efficacy and safety in FH patients. However, comparative rankings and point estimates should be interpreted with caution due to funnel plot asymmetry for LDL-C and imbalances in trial data. Ongericimab demonstrated promising results in HeFH, but further validation is required. Inclisiran's efficacy may be underestimated due to short-term follow-up. Monotherapy with PCSK9 inhibitors has limited efficacy in HoFH patients, highlighting the need for combination therapies. Show less

Lifelong APOB gene inactivation lowers LDL-C and cardiovascular risk, but impairs hepatic lipoprotein export, predisposing to chronic liver disease (CLD). The extent to which common steatogenic factors modulate this risk remains unclear. Moreover, the balance between long-term cardiovascular protection and CLD risk in APOB variant carriers has never been evaluated. Using UK Biobank data, we analysed 241 APOB loss-of-function (LoF) carriers and 410 721 non-carriers, stratified by steatogenic risk factors, including age, sex, diabetes, BMI, alcohol intake and the PNPLA3-rs738409 genotype. Associations with transaminase levels, CLD and cardiovascular (ASCVD) outcomes were assessed using Python and R packages. APOB carriers had ~35% lower LDL-C and apoB levels, along with reduced total triglycerides and Lp(a) (all p < 0.001). Baseline ALT and AST were higher in carriers than in non-carriers (P Long-term exposure to low LDL-C levels due to APOB LoF variants has opposite consequences, reducing ASCVD risk but increasing CLD risk, especially in the presence of diabetes and obesity. These findings highlight the importance of balancing cardiovascular benefit with hepatic safety when considering apoB-targeting therapies. Show less

To develop and assess the efficacy of a rehabilitation-cognition integrated care (RCIC) program for elderly patients with lower limb fractures and mild-to-moderate cognitive impairment. A total of 128 eligible patients during January 2023 to December 2024 were randomly allocated to conventional (n = 64) or integrated care group (n = 64). Both groups received 12 weeks of intervention. Outcomes, including Fugl-Meyer Assessment (FMA), Berg Balance Scale (BBS), Montreal Cognitive Assessment (MoCA), Functional Independence Measure (FIM), and Hospital Anxiety and Depression Scale (HADS) scores, were compared. Serum neurotrophic and neuroinflammatory markers were analyzed pre- and post-intervention. Complications, fall recurrence rates, and nursing satisfaction were recorded. Post-intervention, both groups showed improved FMA, BBS, and FIM scores, with significantly greater improvement in the integrated care group (p < 0.05). HADS-Anxiety (HADS-A) and HADS-Depression (HADS-D) scores decreased significantly more in the integrated care group (p < 0.05). The integrated care group demonstrated higher MoCA scores versus both its own baseline and the conventional care group post-intervention (p < 0.05). Serum BDNF and GDNF levels increased significantly in the integrated care group compared to both time-matched controls and its baseline (p < 0.05), while S100-β and IL-6 levels decreased significantly (p < 0.05). The integrated care group had lower overall complication rates (p < 0.05), comparable fall recurrence (p > 0.05), and higher nursing satisfaction (p < 0.05). The RCIC program significantly enhances motor function, balance, cognition, and psychological status while reducing complications and improving satisfaction in elderly fracture patients with cognitive impairment. Show less

Congenital hypogonadotropic hypogonadism (CHH) is a rare and genetically heterogeneous disorder characterized by absent or incomplete puberty due to impaired gonadotropin-releasing hormone (GnRH) function. A subset of individuals with CHH also present with developmental anomalies, including midline defects such as cleft lip and/or palate (CLP). This study investigates the genetic overlap between CHH and CLP. A total of 336 individuals diagnosed with CHH were clinically assessed for associated phenotypes, including CLP. High-throughput sequencing was performed using a targeted gene panel encompassing known CHH- and CLP-related genes. Variants were analyzed and classified according to the American College of Medical Genetics and Genomics (ACMG) criteria for pathogenicity. CLP was present in 21 patients with CHH (6%). Pathogenic or likely pathogenic variants in genes associated with both CHH and CLP-such as FGFR1 and CHD7-were identified in eight individuals. Furthermore, 17% of the patients with CHH without CLP harbored deleterious variants in genes implicated in clefting, including DVL3, PLCB4, NIPBL, and EDNRA. Evidence of digenic inheritance involving both CHH- and CLP-related genes was observed in multiple cases. FGFR1 variants were the most frequently detected and were commonly associated with anosmia and additional developmental anomalies. These findings highlight a genetic and phenotypic continuum between CHH and CLP, underscoring the involvement of shared developmental pathways. The high prevalence of FGFR1 variants in patients with CHH and CLP supports its role as a pleiotropic gene. Understanding the overlapping genetic mechanisms may enhance diagnostic precision and inform personalized management strategies for affected individuals. Show less

Problematic social media use (PSMU) has emerged as a societal and behavioral concern, especially among young adults. However, individual differences in symptom manifestation remain understudied. The present study adopted a person-centered approach to identify distinct profiles of PSMU and to examine the predictive roles of fear of missing out (FoMO), problematic smartphone use (PSU), age, and sex among a sample of 625 Italian university students aged 18 to 40 years ( Show less