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China's total fertility rate has reached a critically low level, dropping to approximately 1.0 by the end of 2023which is significantly below the population replacement level of 1.5. This decline reflects a marked reduction in fertility intention among reproductive-aged women, exacerbating population aging and threatening long-term labor supply and social sustainability. Despite policy adjustments and governmental support initiatives, intended outcomes have not been realized. Current literature largely focuses on isolated determinants of fertility intention, overlooking heterogeneity within the population. Moreover, the pathways through which psychosocial factors operate across different subgroups remain poorly understood. Data for this study were derived from the 2021 Psychological and Behavioral Investigation of Chinese Residents (PBICR 2021), a nationally representative cross-sectional survey. Latent profile analysis (LPA) was employed to identify subtypes of fertility intention among reproductive-aged women, followed by multinomial logistic regression, which examined factors associated with different profiles. Among 2,973 reproductive-aged female participants, three distinct fertility intention profiles were identified via latent profile analysis: the Fertility Intention Decline Group (25.1%), the Low Fertility Intention Group (51.3%), and the High Fertility Intention Group (23.6%). Multinomial logistic regression analysis revealed that, compared with the Fertility Intention Decline Group, the Low Fertility Intention Group was significantly associated with family type, aged 20-40 years, residential location, having 2 children, and retirement status (all Fertility intention among reproductive-aged women demonstrates significant heterogeneity. This study identified three distinct latent profiles, each characterized by unique patterns of influencing factors. The findings highlight the necessity of moving beyond one-size-fits-all policy approaches and emphasize the importance of developing tailored interventions that account for the specific characteristics and determinants of each subgroup. Show less

Nurses in traditional Chinese medicine (TCM) departments face significant sleep challenges associated with occupational stressors. However, person-centered analyses classifying these sleep patterns remain scarce. This study aimed to identify heterogeneous sleep disturbance subgroups via latent profile analysis (LPA) and evaluate the performance of explainable machine learning models in discriminating these subgroups based on demographic and occupational features. A cross-sectional survey enrolled 7721 nurses from 130 TCM healthcare institutions in Liaoning Province (December 2024). Data encompassed demographic, occupational, and psychological variables obtained via self-administered questionnaires, including the Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance short form 8a. LPA was employed to categorize sleep disturbance patterns. Recursive feature elimination with random forest (RFE-RF) was used to select features associated with subgroup membership for five machine learning models. Models were trained on 70% of the data and evaluated on a 30% independent test set. The optimal classification model (XGBoost) underwent interpretability analysis using Shapley additive explanations (SHAP). LPA identified three subgroups: mild-stable (29.8%), moderate-fluctuating (60%), and severe-persistent (10.2%). Machine learning models achieved test AUCs of 0.71-0.84, with XGBoost demonstrating the highest discriminatory performance (AUC = 0.84, 95%CI: 0.83-0.85) in classifying subgroups. SHAP analysis indicated that monthly income, organizational support, hospital level, self-compassion, and resilience were the top five features contributing to the model's classification output. This study characterized three distinct sleep disturbance subgroups among TCM nurses, with the majority exhibiting moderate symptoms. The sequential application of LPA and explainable machine learning demonstrated robust performance in distinguishing sleep disturbance patterns. Identifying correlates-such as lower income and resilience-may assist nurse managers in stratifying risk and tailoring interventions for those most likely to fall into the severe subgroup. Future longitudinal studies are required to validate the stability of these subgroups and establish causal relationships. Show less

This is a cross-sectional study designed to identify the latent profiles of psychological resilience in elderly patients with fracture and examine the relationship between resilience categories and fear of falling (FOF), thereby informing individualized rehabilitation strategies. A convenience sample was drawn from elderly patients admitted to the Department of Traumatology and Orthopedics at a tertiary general hospital in Beijing between September 2024 and July 2025 due to fall-related fractures. A total of 213 older adults aged 60 and above with fall-related fractures were included. Psychological resilience was assessed using the Connor-Davidson Resilience Scale (CD-RISC), and FOF was measured with the Falls Efficacy Scale-International (FES-I). Latent Profile Analysis (LPA) was used to identify resilience profiles. Logistic and linear regression analyses, adjusting for age, sex, comorbidities, pain level, functional status, and time since fracture/surgery, were performed to explore the relationship between resilience subtypes (entered as a continuous CD-RISC score), demographic and clinical factors, and FOF levels. The age of elderly patients with fall-related fractures was 60–98 (75.28 ± 8.73) years old, and the median age was 74 years old. Three latent resilience profiles were identified: low (33.5%), moderate (22.7%), and high (43.8%) resilience groups. Patients in the high-resilience group exhibited significantly lower FOF scores than those in the other two groups ( Psychological resilience is independently associated with fear of falling among elderly fracture patients, with a clear gradient across resilience profiles. Enhancing resilience, particularly in low-resilience individuals, may be a potential target for intervention, though causal inference is limited by the cross-sectional design and single-center, convenience sampling strategy. Integrating resilience assessment into clinical evaluation could support more holistic rehabilitation planning. ChiCTR2400089221, September 4, 2024. Show less

Physical activity can improve health-related quality of life (HRQoL); however, it is not clear whether this association is direct or indirect. The aims of this study were to examine the associations of daily movement behaviours with physical and mental HRQoL in older adults, and the mediating role of muscle strength and body composition on it. Three hundred thirty-four community-dwelling older adults wore the Intelligent Device for Energy Expenditure and Activity for two consecutive days to quantify time spent in sedentary behaviour (SB), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA). HRQoL was assessed using the 12-Item Short-Form Health Survey, yielding physical (PCS) and mental (MCS) component scores. For muscle strength, a handgrip dynamometer and the Sit-to-Stand test were used. Body mass index (BMI), waist circumference, and estimates of skeletal muscle mass and fat mass by bioelectrical impedance were included as body composition variables. Association analyses were examined using linear regression models, and for mediation analysis, structural equation modelling was used. MVPA was positively associated with PCS [β (95%CI): 0.39 (0.19, 0.59)], whereas no significant associations were observed between MVPA, LPA, or SB and MCS. The association between MVPA and PCS was partially mediated by lower-limb muscle strength and fat mass percentage [8.5% (z = 1.753, p = 0.080) and 28.9% (z = 1.912, p = 0.056), respectively], and fully mediated by skeletal muscle mass normalized by BMI [28.2% (z = 2.016, p = 0.044)].Regular engagement in MVPA is positively associated with the physical component of HRQoL in older adults, both directly and indirectly through muscle strength and skeletal muscle mass. Show less

Post-traumatic stress disorder (PTSD) causes debilitating nightmares, flashbacks and anxiety stemming from a catastrophic, often life-threatening traumatic event. Originally described in soldiers exposed to the horrors of battle, PTSD is now recognized in civilian victims of assault, natural disasters and mass casualty events. Most people experiencing trauma do not develop PTSD, so understanding neurobiological mechanisms is crucial to predicting risk and developing targeted treatments. There have been many studies seeking to find biomarkers for PTSD, and their results have converged on several brain regions, molecular pathways and neuropsychological functions. In this review, we focus on selected findings about the glucocorticoid receptor (GR), the chaperone protein FKBP51 (FK506 binding protein 51), BDNF (brain-derived neurotrophic factor), fear memory reconsolidation and epigenetic regulation of gene expression in the hypothalamic-pituitary-adrenal (HPA) axis, amygdala and hippocampus. Together, these disparate aspects of brain function provide an emerging model for understanding the etiology and pathophysiology of PTSD. Avoidance of lethal threats is fundamental for survival, and this stringent evolutionary requirement has conserved many components of fear memory storage and behavioural response to danger. PTSD research can therefore rely on non-human animal model systems with better face and construct validity than most other psychiatric disorders. With this advantage, advances in PTSD biomarker identification are likely closer to clinical translation than in other mental illnesses. We attempt to highlight the most promising biomarkers that could be targeted by novel treatments and propose a map for future research work. Show less

Pulmonary artery sling (PAS) is a rare congenital vascular anomaly, in which the left pulmonary artery arises aberrantly from the right pulmonary artery and courses between the trachea and esophagus, often causing tracheobronchial compression. It is frequently considered within the spectrum of vascular rings. Prenatal diagnosis remains challenging yet crucial for optimizing perinatal management and neonatal outcomes. This case report illustrates the enhanced diagnostic capability achieved by integrating conventional two-dimensional (2D) ultrasound with spatiotemporal image correlation (STIC) technology for the accurate prenatal identification of PAS. A 33-year-old gravida 2 para 0 woman was referred for routine fetal assessment at 31 weeks of gestation. Initial 2D ultrasonography in the three-vessel tracheal view revealed an anomalous vascular configuration, suggesting the left pulmonary artery (LPA) originating from the right pulmonary artery (RPA). To confirm the diagnosis and delineate the vascular course, STIC technology was employed. The STIC volumetric acquisition and subsequent multi-planar reconstruction unequivocally demonstrated the LPA arising from the RPA and coursing posteriorly behind the trachea, thereby confirming the diagnosis of PAS. A comprehensive fetal echocardiogram excluded associated intracardiac anomalies. Following extensive parental counseling, the pregnancy continued uneventfully. The infant was delivered via elective cesarean section at 38 The synergistic use of routine 2D ultrasound and STIC technology provides a robust, clinically accessible method for the precise prenatal diagnosis of fetal PAS. This integrated imaging approach facilitates definitive diagnosis, enhances parental counseling, enables coordinated multidisciplinary perinatal planning, and ensures timely surgical intervention, all of which are pivotal for achieving favorable long-term outcomes in affected infants. Show less

Peripheral artery disease (PAD) is a major manifestation of systemic atherosclerosis and affects vascular health in older adults. Dyslipidaemia contributes significantly to PAD, but the predictive value of composite lipid indices remains unclear. The non-high-density lipoprotein cholesterol (non-HDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (NHHR) reflects the balance between atherogenic and protective lipoproteins. This study aimed to explore the association between the NHHR and PAD among vascular surgery inpatients aged ≥50 years in Kunshan, China. This retrospective cross-sectional study included 3,532 patients (aged ≥ 50 years) hospitalized at the Affiliated Kunshan Hospital of Jiangsu University, Suzhou, from December 2017 to August 2024. NHHR, calculated as (total cholesterol - HDL-C)/HDL-C, was the exposure variable; PAD, defined as PAD-like symptoms with an ankle brachial index < 0.9, was the outcome. Covariates included age, sex, lipoprotein(a) level [Lp(a)], apolipoprotein A1 level (Apo A1), alanine aminotransferase (ALT) level, neutrophil count (NEUT), hypertension status, diabetes status, smoking status, and alcohol consumption status. Multivariate logistic regression, smooth curve fitting, and threshold analyses were performed. After adjustment for confounders, the NHHR was nonlinearly associated with PAD (OR = 0.77; 95% CI: 0.65-0.93; The NHHR was associated with the presence of PAD, with the evidence suggesting a nonlinear relationship and potential sex-specific differences. Given the retrospective cross-sectional design, this association does not support causal inference or strong predictive claims. The NHHR may help identify individuals who could benefit from further clinical evaluation for PAD, but prospective studies are needed to confirm its clinical relevance before its routine application. Show less

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for type 2 diabetes mellitus (T2DM) and obesity, show promising potential as a novel treatment for depression, particularly in patients with comorbid metabolic disorders. This narrative review examines the bidirectional relationship between obesity and depression, driven by shared mechanisms such as chronic low-grade inflammation, hypothalamic-pituitary-adrenal axis dysregulation, and impaired neuroplasticity. GLP-1 RAs, including liraglutide and exenatide, demonstrate neuroprotective effects by enhancing brain-derived neurotrophic factor expression and synaptic plasticity, alongside anti-inflammatory properties that reduce proinflammatory cytokines (e.g., tumor necrosis factor-alpha and interleukin-6). They also modulate serotonin turnover in mood-regulating brain regions, mirroring selective serotonin reuptake inhibitors. Preclinical studies in animal models reveal improved behavioral outcomes, while human observational studies and limited clinical trials, such as the LEAD-3 trial, report enhanced mood and quality of life in T2DM and obesity patients. However, challenges, including high treatment costs ($800-$1000/month), injectable administration, and needle-related anxiety, limit patient adherence, and clinical adoption. The lack of large-scale randomized controlled trials targeting depression as a primary outcome further hinders definitive conclusions. This review highlights GLP-1 RAs' potential to address both metabolic and depressive symptoms, offering a holistic approach to managing these interconnected conditions. Future research should focus on long-term efficacy, optimal dosing, and overcoming adherence barriers to establish GLP-1 RAs as a viable psychiatric treatment. Show less

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers. Show less

The statins remain the foundation of lipid management because they lower low-density lipoprotein cholesterol (LDL-C) and prevent cardiovascular events, and guidelines recommend stepwise intensification, often with ezetimibe first, when targets are not met or when intolerance limits dosing. This review introduces a mechanism-first, phenotype-guided framework that links add-on therapies to the dominant driver of residual risk, LDL-C, triglyceride-rich lipoproteins, elevated lipoprotein(a), or inherited dyslipidemia while integrating trial evidence with clinical practicality. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies remain the best-validated add-on for very high-risk patients. FOURIER and ODYSSEY OUTCOMES demonstrated event reduction with evolocumab or alirocumab on background statin therapy. For patients who cannot tolerate adequate statin doses, bempedoic acid provides liver-selective inhibition of adenosine triphosphate (ATP)-citrate lyase, and CLEAR Outcomes showed fewer major cardiovascular events in statin-intolerant populations. Inclisiran extends PCSK9 pathway suppression through hepatic small interfering RNA (siRNA) and enables durable LDL-C reduction with twice-yearly maintenance dosing, offering an adherence-oriented alternative while outcomes data mature. Angiopoietin-like protein 3 (ANGPTL3)-directed therapies (evinacumab and investigational RNAi agents such as zodasiran) lower atherogenic lipoproteins through largely LDL receptor independent biology. They expand options for refractory disease, including homozygous familial hypercholesterolemia. Apolipoprotein C-III (ApoC-III) inhibitors (olezarsen and plozasiran) drive large triglyceride reductions that can be decisive in severe hypertriglyceridemia and pancreatitis-prone syndromes. Next-generation cholesteryl ester transfer protein (CETP) inhibition (notably obicetrapib) has re-emerged as an oral strategy with substantial lipid effects as outcomes programs progress. High-dose eicosapentaenoic acid (EPA) (icosapent ethyl) has the clearest triglyceride-focused outcomes signal; REDUCE-IT showed significant ischemic event reduction in statin-treated patients with persistent hypertriglyceridemia. Early Show less

Improved internet access has exposed rural adolescents in China to a greater risk of internet addiction. However, existing studies seldom examine the relationship between dynamic changes in internet addiction and psychosocial maladjustment. This study aims to explore the transition patterns of internet addiction and its associations with emotional and interpersonal problems over time. A one-year longitudinal survey was conducted among 782 middle school students in rural China. Latent Profile Analysis (LPA) was conducted to identify internet addiction profiles at two time points. Latent Profile Transition Analysis (LPTA) was then used to examine the transition patterns between profiles over time. Subsequently, statistical analyses were conducted to explore how these transitions were associated with emotional and interpersonal problems. Three profiles of internet addiction were identified: minimal-internet addiction, low-internet addiction, and high-internet addiction. Based on LPTA, most adolescents with higher internet addiction at T1 shifted to lower-severity profiles over time (high → minimal: 35.3%; low → minimal: 39.8%; high → low: 33.3%), while some with initially lower levels transitioned to more severe profiles (minimal → high: 6.9%; low → high: 12.2%; minimal → low: 25.7%). Transition into higher addiction profiles predicted increased depression, anxiety, and poorer relationships with parents, peers, and teachers. Conversely, reductions in addiction were linked to improved depressive symptoms. Changes in internet addiction have an impact on adolescent psychosocial maladjustment. Early detection and flexible interventions are essential in rural settings. Show less

This study aimed to investigate the latent profiles of clinical nurse preceptors (CNPs)' compassion fatigue (CF), identify the influencing factors, and examine their association with work alienation. Between July and August 2025, 340 nurse preceptors from a tertiary grade A general hospital in Zhejiang Province were recruited as participants using convenience sampling. The Chinese version of the Professional Quality of Life Scale Version 5 (ProQOL-5) and the Work Alienation Scale (WAS) were used to assess compassion fatigue and work alienation, respectively. Demographic information was also collected from the participants. Latent Profile Analysis (LPA) was employed to identify potential profiles of compassion fatigue. After screening variables through univariate analysis and multicollinearity tests, multinomial logistic regression was used to assess the influencing factors. Furthermore, a one-way ANOVA was conducted to examine differences in work alienation among different potential profiles, and the results were interpreted based on the job demands-resources (JD-R) model theoretical framework. A total of 320 CNPs were included in the final analysis. The findings of the latent profile analysis indicated that three latent profiles of CNPs' compassion fatigue were identified: high-satisfaction-low-exhaustion group (n = 56, 17.5%), moderate compassion fatigue group (n = 160, 50%), and severe exhaustion group (n = 104, 32.5%). Multinomial logistic regression analysis showed that age, marital status, education, years of preceptorship, experience, employment type, and professional title were significant predictors of compassion fatigue among CNPs. There were statistically significant differences in the work alienation scores among the three latent profiles (P < 0.001). CNPs' compassion fatigue can be categorised into three types, with significant heterogeneity observed among them. Notable differences exist in work alienation among CNPs with different compassion fatigue types. These findings suggest that clinical managers and educators should develop targeted interventions and support systems based on these circumstances. Therefore, formulating such management strategies is crucial for alleviating work alienation among CNPs and will help improve nurse retention rates and the quality of clinical education. Show less

Neuroinflammation is a central contributor to Huntington's disease (HD) pathogenesis and represents a promising therapeutic target. Laquinimod, an oral immunomodulator with demonstrated neuroprotective effects in preclinical models, has been investigated as a potential treatment for HD. This review critically appraises its preclinical and clinical evidence. A systematic search (January 2025) was conducted in PubMed, Scopus, Embase, Cochrane Library, and Web of Science using terms including "Huntington's disease," "laquinimod," and "quinoline-3-carboxylic acid." Preclinical and clinical studies evaluating laquinimod in HD were included. Due to heterogeneity, findings were synthesized qualitatively. Of 2638 records identified, 10 studies met the inclusion criteria. Preclinical data showed laquinimod improved motor function, reduced neuroinflammation, and promoted myelination, likely via microglial modulation, NF-κB suppression, and increased BDNF expression. Effects on myelin integrity and inflammatory markers were inconsistent. In vitro studies showed limited, variable cytokine modulation in HD patient-derived cells. Clinical trials did not demonstrate significant improvements in motor or functional outcomes, though one study reported minor cognitive and behavioral benefits. Preclinical evidence suggests laquinimod may modulate motor, inflammatory, and myelination pathways in HD; however, clinical evidence shows no meaningful benefit. Data on long-term safety remain limited. Larger, well-designed trials using standardized biomarkers are needed to clarify its therapeutic potential. Show less

Colorectal cancer (CRC) is a highly aggressive malignancy prone to liver metastasis, which significantly worsens prognosis of patients. Autophagy supports tumor cell survival by meeting metabolic demands and evading programmed cell death. This study aimed to develop a prognostic risk signature for CRC patients by integrating autophagy- and metastasis-related genes and to investigate its association with the tumor immune microenvironment and implications for immunotherapy. Weighted gene co-expression network analysis (WGCNA) identified candidate genes related to autophagy and liver metastasis. Univariate Cox and LASSO regression analyses were employed to develop a risk signature in the TCGA cohort, which was subsequently validated using an independent GEO cohort. Functional enrichment, immune infiltration, the heterogeneity and dynamics of macrophages and A prognostic risk signature incorporating six biomarkers ( In our study, we developed and validated a novel autophagy- and liver metastasis-associated prognostic signature for CRC. The risk signature effectively predicts alterations in the tumor immune microenvironment, immunotherapy, chemotherapy sensitivity and intercellular communication across different risk groups. Importantly, our findings reveal that autophagy and liver metastasis synergistically foster an immunosuppressive microenvironment, highlighting a potential target for therapeutic intervention. Show less

Vascular graft fibrosis can cause a decrease in cellular infiltration and capillary ingrowth in vascular walls. It can also lead to vascular stiffening. As such, there are still no vascular grafts that can be used in blood vessels where their diameters are less than 6 mm in patients. Although various approaches have been evaluated to mitigate implant-associated fibrosis, effective treatments remain quite limited. In this study, we demonstrated that Apolipoprotein E (APOE) significantly increased during vascular regeneration after graft implantation Show less

Untargeted mass spectrometry remains underutilised for blood-based biomarker discovery in dementia research from large cohorts, where affinity-based approaches dominate. To address this, we examined mass-spectrometry-derived proteomic correlates of cognitive function, genetic predisposition to cognitive health, Show less

Alzheimer's disease (AD) is the most common cause of dementia worldwide, affecting over 55 million individuals and projected to rise drastically in the coming decades. Characterized by progressive cognitive decline and memory impairment, AD involves complex pathological mechanisms including amyloid-beta (Aβ) plaque accumulation, neurofibrillary tangles (NFTs) of hyperphosphorylated tau, and chronic neuroinflammation. This comprehensive review aims to provide a foundational understanding of the molecular, genetic, and immunological underpinnings of AD, with a focus on pathogenic proteins, glial cell responses, and current monoclonal antibody (mAb)-based therapeutic strategies. Literature on key pathological players such as Aβ, tau, microglia, and astrocytes was mentioned to explain their roles in neurodegeneration. The impact of key genetic mutations (APP, PSEN1, PSEN2, APOE, BACE1, MAPT) was outlined. Additionally, recent clinical trial data of anti-Aβ monoclonal antibodies (aducanumab, lecanemab, donanemab) were reviewed, with comparative analysis of efficacy, safety, and trial outcomes. Neuroinflammation, mediated by activated microglia and astrocytes, exacerbates Aβ and tau pathology, contributing to synaptic loss and neuronal death. Genetic mutations alter APP processing and promote plaque formation. Monoclonal antibodies show promise in reducing Aβ burden and slowing cognitive decline: donanemab achieved 60% slower decline in mild cognitive impairment, while lecanemab showed 27% cognitive benefit in early AD. Aducanumab, despite initial promise, was discontinued in 2024 due to limited efficacy and safety concerns. Adverse events like amyloid-related imaging abnormalities (ARIA), particularly in APOE-4 carriers, remain significant. AD pathology is multifactorial, involving an interplay between protein aggregation, immune dysregulation, and genetic risk. While mAb therapies mark progress in disease modification, their success depends on patient stratification, early intervention, and safety profiling. Future directions must emphasize combinatorial and personalized approaches incorporating early biomarkers, neuroimaging, and emerging technologies to effectively combat the rising global burden of AD. Show less

Individuals with chronic conditions have persistent, co-occurring symptoms affecting quality of life. Understanding symptom severity susceptibilities is critical for early risk identification, but gaps remain among racial and ethnic minority men with chronic conditions. As such, this study identifies symptom severity profiles in non-Hispanic Black and Hispanic men based on five common symptoms (fatigue, pain, shortness of breath, sleep disturbance, depression) and its associated demographic, clinical, and modifiable sociobehavioral risk factors. Online survey data from 1,982 men aged 40 and older with chronic conditions was analyzed using latent profile analysis (LPA) to identify symptom severity profiles. LPA revealed three symptom severity profiles: lowest (63.4%); moderate (13.9%); and highest (22.7%). Multinomial and binary logistic regressions were used to analyze demographic, clinical, social, and behavioral factors associated with symptom severity profiles. Compared to men in the lowest symptom severity profile, men in the highest symptom severity profile were younger (OR = 0.98, p < 0.001), had lower incomes (OR = 0.95, p = 0.028), had more comorbidities (OR = 1.92, P = 0.001), had more medications (OR = 1.09, P = 0.012), reported current tobacco (OR = 1.55, P < 0.001) or cannabis (OR = 1.45, P = 0.011) use, experienced more social disconnectedness (OR = 1.34, P < 0.001), and had poorer self-management efficacy (OR = 0.93, P < 0.001). Compared to men in the moderate profile, men in the highest profile had lower education (OR = 0.53, P = 0.002), more comorbidities (OR = 1.77, P = 0.018), higher medication use (OR = 1.11 P = 0.009), and increased cannabis use (OR = 1.56, P = 0.017). Findings highlight diverse symptom experiences and key factors that can be targeted in prevention and treatment strategies to reduce symptom severity within these subpopulations. Show less

The annual ~36,000 prostate cancer (PCa) deaths represent a large clinical unmet need and a call for deeper understanding of PCa metastasis. Epithelial-mesenchymal-transition (EMT) has been used to model metastatic behaviors in numerous cancers including PCa. One hallmark of EMT is cell cycle suppression, but how EMT impacts PCa proliferation remains unclear primarily due to the lack of appropriate models. We transiently induced Snail1 (SNAI1) expression, an EMT driver expressed in PCa, at physiological levels in three PCa cells lines, C4-2B, 22Rv1, and DU145. We used RNA-seq, ChIP-Seq, bioinformatics, qRT-PCR, shRNA, and immunoblotting to identify mechanisms of Snail1-driven inhibition of proliferation. Snail1 suppressed proliferation and G2/M cell cycle progression, without affecting cell death. Mechanistically, Snail1 upregulated expression of CEBPγ, ERG1, FOXO1, cyclin G1, p21, stress genes SESN3 and SOD3, apoptotic programmers Puma, Bax, and Noxa, and senescence-related laminB1, and downregulated Ki67, cyclins A2 and B2. ChIP-Seq data identified Snail1 direct binding to p21, cyclin B2 and G1, EGR1, and CEPBγ promoters. EGR1 induced FOXO1, and EGR1 was required for Snail1-induced SOD3 and Puma, and suppression of Caspase 3 to prevent apoptosis. The EGR1/FOXO1 axis induced BAX, Noxa, and SESN3. CEBPγ was required for Snail1 induction of Lamin B1 to block Snail1-induced senescence. We identified three new major downstream targets of Snail1 that improve our understanding of the role of EMT in limiting stress signaling, apoptosis, and senescence during cell cycle suppression to create a vulnerability for therapeutic targeting. Show less

Thoracic aortic dissection (TAD) is a life-threatening acute vascular condition with high morbidity and mortality. Endothelial cells (ECs) are critical for maintaining vascular homeostasis, yet the role of endothelial-to-mesenchymal transition (EndoMT), a key cell-fate process in vascular development and disease, in TAD remains poorly defined. Furthermore, the functional role of PDK4 (pyruvate dehydrogenase kinase 4) as a driver of this pathological cell-fate transition has not been elucidated. To delineate the mechanistic contribution of EndoMT to TAD, we integrated transcriptomic profiling and immunofluorescence analysis in human aortic specimens and a β-aminopropionitrile-induced murine model. Following the identification of PDK4 as a critical downstream effector of EndoMT signaling via RNA-sequencing and chromatin immunoprecipitation assays, its functional role was validated using conditional EC-specific knockout mice and adeno-associated virus-mediated endothelial gene modulation. Serum samples were collected, and ELISA was used to measure levels of endothelial injury markers for assessing EC-dysfunction. In addition, therapeutic potential was assessed using dichloroacetate, a small-molecule PDK4 inhibitor. A robust activation of the EndoMT gene program was observed in both human TAD specimens and murine aortic tissues, characterized by the loss of endothelial identity and acquisition of mesenchymal traits. Transcriptomic screening pinpointed PDK4 as a critical mediator upregulated during EndoMT. Mechanistically, we demonstrated that the transcription factor Our findings demonstrate that the pathological EndoMT program is activated in ECs by PDK4, which aggravates TAD development in β-aminopropionitrile-induced mouse models, highlighting PDK4 as a promising therapeutic target for TAD. Show less

Probiotics are increasingly recognized for their health-promoting effects, yet their performance in unconventional fermentation systems such as halophyte-based substrates remains poorly understood. Halophytes, salt-tolerant plants rich in phenolics and other bioactive compounds, impose selective pressures that may favor robust and stress-tolerant microorganisms. In this study, we assessed the probiotic potential of selected lactic acid bacteria and yeast strains, including [Image: see text] Show less

Dyslipidemia is a major risk factor for the development of NAFLD, atherosclerosis and cardiovascular diseases. Rosuvastatin (ROS) is a lipid-lowering drug that protects against the development of NAFLD and atherosclerosis. However, the mechanism of this protection remains obscure. Therefore, the current study aims to explore the mechanism by which ROS-loaded glycerosomes (ROS-GLY) protect against NAFLD and atherosclerosis. Hence, for this purpose, hepatic lncRNA-H19/miR-130a/PPAR-γ and aortic PPAR-γ/LXRα/ABCA1 signaling pathways were assessed. In addition, these target pathways were predicted using molecular docking analysis. Thirty-five male Sprague Dawley rats were separated into control, dyslipidemic (poloxamer 407 (P 407)), P 407+ROS-GLY, P 407+NC, and P 407+ROS-GLY+NC groups. ROS-GLY improved lipid profile, hepatic MDA, SOD, catalase and total antioxidant capacity (TAC) in compared to P 407 group. In the dyslipidemic group, ROS-GLY downregulated hepatic lncRNA-H19 expression which leads to an upregulate of the miR-130a level and subsequent reduction of the PPAR-γ level. Consequently, the hepatic expression level of lipogenic genes such as, ACC-1, FASN and SCD-1 was significantly downregulated in the ROS-GLY group than the dyslipidemic one. Aortic PPAR-γ/LXRα/ABCA1 signaling pathway was significantly upregulated in the ROS-GLY group compared to the dyslipidemic group. Furthermore, ROS-GLY modulated IL-6 and IL-10 immunoprotein expression in hepatic and aortic tissues. Interestingly, ROS showed a substantial binding affinity with PPAR-γ, LXR-α, and FASN, according to a molecular docking study. The current study indicated that ROS-GLY protected against the progression of NAFLD and atherosclerosis in dyslipidemic rats via modulation of lipid profile, oxidative stress, pro-/anti-inflammatory cytokines, hepatic lncRNA-H19/miR-130a/PPAR-γ, and aortic PPAR-γ/LXRα/ABCA1 signaling pathways. Show less

Based on epidemiological and genetic studies in recent decades, lipoprotein(a) (Lp(a)) has been accepted as a causal risk factor for atherosclerotic cardiovascular disease and aortic stenosis. Although inter-ethnic differences exist, Lp(a) level ≥50 mg/dL is commonly reported to indicate elevated cardiovascular risk. Blood Lp(a) levels are largely determined based on genetic background, and the kringle IV type 2 repeat variant is a major factor. Lp(a) is structurally similar to low-density lipoprotein (LDL) but also contains apolipoprotein(a) (apo(a)), which includes kringle domains associated with diverse effects depending on particles and individuals. The LDL-like property of Lp(a) and effect of apo(a) on vascular cells can promote atherosclerosis. Apo(a) competes with plasminogen and can inhibit the role of plasmin during fibrinolysis. Furthermore, oxidized phospholipids on apo(a) may induce oxidative stress to enhance atherosclerosis and can affect valve calcification. Trials on new therapeutics targeting Lp(a) RNA, including antisense oligonucleotide (e.g., pelacarsen), siRNAs (e.g., olpasiran, lepodisiran, and zerlasiran), and small molecules (e.g., muvalaplin), are under way. Depending on the study or dose, these agents lowered Lp(a) levels by 80-100% compared with the control; however, results of clinical outcomes have yet to be reported. Show less

Suicidal ideation (SI) and behavior are complex phenotypes, with multiple contributing risk-factors. This study used longitudinal data from the Million Veteran Program Mental Health Survey to identify SI profiles among Veterans based on trajectories of ideation and depression severity and compared them to a non-suicidal (no-SI) control group. Latent profile analysis (LPA) was performed to identify SI profiles using data from Veterans (n = 34,322) endorsing SI in their electronic health record. LPA identified four highly reproducible SI profiles: mild ideators with and without depression, variable ideators, and persistent ideators. Veterans across the SI profiles were significantly more likely to have diagnoses of suicidal ideation or behavior, mental disorders, and TBI compared to Veterans with no-SI. The variable ideators showed higher rates of comorbid conditions. The mild ideators without depression and persistent ideators had a significantly higher proportion of deaths by suicide than the no-SI Veterans. European and African American GWAS and pan-ancestry meta-analyses of SI profiles compared to no-SI controls were also performed, which identified genome-wide significant loci across all SI profiles proximal to genes implicated in auditory and vestibular functioning, Alzheimer's, diabetes, and asthma. In summary, SI profiles identified were associated with novel genetic variants not identified by previous suicide GWAS studies. Additionally, Veterans within the mild SI profile that did not present with high-risk comorbidities had the highest rate of suicide deaths, indicating the need for upstream suicide risk prevention interventions across the SI risk continuum. Show less

Type 2 Diabetes Mellitus (T2DM) is a widespread metabolic disorder that can affect brain health, primarily through the damaging effects of prolonged hyperglycemia. This condition increases oxidative stress (OS), neuroinflammation, and neuroapoptosis, ultimately impairing cognitive function. Acrylamide (ACY), a neurotoxicant formed during high-temperature food processing and present in cigarette smoke, may further aggravate these neurological disturbances. The present experiment examined the exacerbating effects of T2DM and ACY exposure on cognitive function, neurodegeneration, OS, neuroinflammation, and neuroapoptosis in diabetic rats. T2DM was induced via intraperitoneal injections of nicotinamide and streptozotocin, followed by daily oral doses of ACY for a month. Behavioral assessments (EPM, NOR, and Y-maze) evaluated cognitive performance. Brain tissues were analyzed for biochemical markers of neurodegeneration (GSK-3β, AChE, BACE1), OS (MDA, GSH, Catalase), neuroinflammation (NF-κB, TNF-α, PGE2, COX-2), and neuroapoptosis (Bcl-2, Bax, Caspase-3). Immunohistochemistry of Bcl-2, Bcl-6, CD138, and NF assessed structural brain changes. Results indicated that T2DM and ACY exposure significantly increased the incidence of neurological disturbances. Notably, through increased COX-2, PGE2, MDA, Bax, Bcl-6, Caspase-3, and cognitive decline deficits. This study highlights the harmful neurotoxic amplification of T2DM and ACY exposure, emphasizing the importance of public health measures to reduce ACY exposure through dietary and lifestyle changes, particularly among T2DM populations. Further research into neuroprotective strategies and underlying mechanisms is necessary. Show less