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This study presents the phylogenetic and antimicrobial susceptibility characterization of Mycobacterium monacense, a rare nontuberculous mycobacterium (NTM), cultured from clinical extrapulmonary samples. Eight Mycobacterium monacense isolates were identified between 2019 and 2023 in the Western Cape province of South Africa. Whole-genome sequencing (WGS) was applied to assess phylogenetic relatedness, identify virulence factors, and characterize the resistome of the isolates. Antimicrobial susceptibility testing (AST) was performed using the GenoType NTM-DR line probe assay (LPA), Sensititre minimum inhibitory concentrations (MIC) plates, and the proportional method based on critical concentrations. Spatial distribution of cases was mapped using ArcGIS software. Spatiotemporal distribution patterns indicated the presence of circulating clones confined within specific geographical areas. Plasmids coding for ferredoxin and cytochrome P450 genes were identified in one cluster, which notably lacked the chromosomal mbtH gene involved in siderophore biosynthesis for iron acquisition. In contrast, isolates grouped in a second cluster harbored the mbtH chromosomal gene but lacked these plasmid-associated elements. LPA and broth microdilution showed that all Mycobacterium monacense isolates were susceptible to aminoglycosides, fluoroquinolones, and macrolides, but generally exhibited elevated MICs against β-lactam antibiotics. Phenotypic AST indicated that drugs commonly used to treat Mycobacterium tuberculosis complex (MTBC), namely bedaquiline, linezolid, and rifampicin, are effective against Mycobacterium monacense. Mycobacterium monacense in extrapulmonary cultures accentuates the need for improved diagnostics and enhanced clinical awareness of infections with rare NTM. WGS highlights the potential significance provided by plasmid-encoded genes. Current treatment regimens for MTBC exhibit therapeutic efficacy against Mycobacterium monacense isolates. Show less

Cardiovascular disease (CVD) is the leading cause of death among older adults, with sedentary behavior (SB) as a key modifiable risk factor. While physical activity (PA) is associated with cardiovascular health, evidence remains limited on the specific effects of replacing SB with PA of varying intensities. To systematically review evidence on the cardiovascular effects of substituting SB with PA in adults aged 65 and older using isotemporal substitution modeling (ISM). Following PRISMA guidelines, seven databases were searched up to April 2025. Risk of bias was assessed using the JBI tool, and a narrative synthesis was conducted. Eighteen observational studies (15 cross-sectional, 3 cohorts) using ISM were included. Replacing 10-60 min of SB with moderate-to-vigorous PA (MVPA) was associated with more favorable in blood pressure, triglycerides, waist circumference, inflammatory markers (CRP, IL-6, GDF-15), and insulin sensitivity (HOMA-IS, Matsuda-ISI). Light-intensity PA (LPA) showed modest associations, particularly among frail or mobility-limited individuals. A daily substitution of 30 min was identified as a feasible reference window, with ≥60 min linked to additional vascular and autonomic benefits. Replacing SB with PA, especially MVPA, was consistently associated with favorable cardiovascular profiles in older adults. Even brief substitutionsmay be beneficial, supporting intensity-stratified public health strategies and refinement of physical activity guidelines for aging populations.Because most included studies were cross-sectional, these findings should be interpreted as associations rather than definitive causal effects, and reverse causation remains a plausible concern. https://www.crd.york.ac.uk/prospero/view/CRD420251021829/1/0, PROSPERO CRD420251021829. 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

T2DM is characterized not only by chronic hyperglycemia but by a complex disturbance in triglyceride-rich lipoprotein (TRL) metabolism. Among the resulting lipid fractions, remnant cholesterol (RC) has emerged as a potentially independent atherogenic driver that persists despite optimal low-density lipoprotein cholesterol (LDL-C) control. Growing evidence suggests that RC integrates metabolic dysregulation, insulin resistance (IR), and inflammatory signaling, thereby contributing to the "residual risk" of vascular complications in DM. To evaluate whether RC functions as an independent atherogenic lipoprotein in T2DM and to assess its clinical implications for risk prediction and therapeutic targeting. This narrative review examined relevant cohort studies, genetic analyses, mechanistic experiments, and clinical trials published in the last decade with emphasis on RC definitions, measurement approaches, associations with macrovascular and microvascular outcomes, and therapeutic modulation. RC elevation in T2DM reflects impaired TRL clearance driven by IR, hepatic VLDL overproduction, and adipose lipolysis. Across large cohorts, RC consistently predicts incident T2DM, major cardiovascular events, renal deterioration, and peripheral arterial disease independent of LDL-C, triglycerides, HbA1c, and inflammatory markers. RC trajectories and visit-to-visit variability further strengthen risk discrimination, suggesting that dynamic fluctuations reflect underlying metabolic instability. Thresholds associated with vascular injury vary across populations (≈0.56-0.80 mmol/L). Therapeutically, high-intensity statins, EPA-based therapy, and emerging APOC3/ANGPTL3 inhibitors lower RC to varying degrees, yet outcome trials targeting RC specifically remain scarce. RC represents a distinct atherogenic entity in T2DM. Its strong and independent associations with cardiovascular and renal events position it as a critical, yet underrecognized, contributor to diabetic vascular risk. Incorporating RC into routine risk assessment and exploring targeted interventions may bridge the persistent gap between LDL-C lowering and actual event reduction. Future studies should prioritize standardized measurement, mechanistic elucidation, and randomized trials directly testing whether lowering RC can modify clinical outcomes. Show less

To explore the latent profiles, core associated factors, and complex mechanisms of work ability among healthcare workers in large tertiary hospitals in China. A cross-sectional study was conducted from July to October 2025. A convenience sample of 1,590 healthcare workers from a large tertiary hospital in Shaanxi Province was assessed using the Work Ability Index (WAI), the Maslach Burnout Inventory-General Survey (MBI-GS), and the Pittsburgh Sleep Quality Index (PSQI). Latent profile analysis (LPA) was employed to identify potential categories of work ability. Multivariable logistic regression analysis was performed to determine independently associated factors and to construct a nomogram prediction model. An additive interaction model and structural equation modeling (SEM) were used to analyze the joint effect and the influential pathways of job burnout and sleep disorder. LPA identified two distinct categories: "Good Work Ability" (73%) and "Poor Work Ability" (27%). Multivariable regression analysis indicated that job burnout (OR = 3.770, 95% CI: 2.510-5.661) and sleep disorder (OR = 2.890, 95% CI: 2.121-3.939) were the factors most strongly associated with poor work ability. Longer working years (≥21 years) and higher professional titles (intermediate/senior) were also associated with an increased likelihood of poor work ability. In contrast, higher education (master's degree or above) and regular physical exercise were associated with a decreased likelihood. The predictive nomogram model demonstrated good discriminative ability (AUCs of 0.781 and 0.740 for the training and validation sets, respectively) and clinical utility. Interaction analysis revealed a significant positive additive interaction between job burnout and sleep disorder (RERI = 5.164, AP = 47.453%). SEM supported a model in which job burnout was not only directly and negatively associated with work ability ( Among healthcare workers in large tertiary hospitals in China, job burnout and sleep disorder are two core and synergistic factors associated with work ability. The prediction model based on multiple factors can provide a practical tool for the early identification of high-risk individuals. Future occupational health intervention programs need to adopt integrated strategies, targeting both the alleviation of job burnout and the improvement of sleep quality as dual core objectives, and implement precise prevention and control for key populations such as those with long service years and high professional titles to maintain and enhance the work ability of healthcare workers. Show less

Elevated lipoprotein(a) [Lp(a)] is a genetically determined, causal risk factor for atherosclerotic cardiovascular disease, but effective therapies remain limited. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are primarily used to lower low-density lipoprotein cholesterol (LDL-C), yet their effects on Lp(a) have been inconsistently reported. This umbrella review synthesizes meta-analytic evidence on PCSK9 inhibitors and Lp(a). We systematically searched PubMed, Embase, Web of Science, and Cochrane Library through April 2025 for meta-analyses of randomized controlled trials (RCTs) comparing PCSK9 inhibitors (alirocumab, evolocumab, inclisiran) with placebo or standard therapy. The primary outcome was mean percentage change in Lp(a). Methodological quality was assessed using the Assessment of Multiple Systematic Reviews 2 (AMSTAR-2), and evidence certainty was graded with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Overlap of primary trials was quantified using the Corrected Covered Area (CCA), and sensitivity analyses were performed to account for overlapping evidence. Twenty-one meta-analyses (116 RCTs; 231,796 participants) were included. The PCSK9 inhibitors consistently reduced Lp(a): evolocumab (29.68-46.68%; high certainty), alirocumab (18.55-26.46%; high certainty), and inclisiran (18.00%; high certainty). Higher biweekly doses yielded larger decreases (e.g., alirocumab 150 mg: 24.6%; evolocumab 140 mg: 26.8%, high certainty). Reductions were dose-dependent and broadly consistent across populations, comparators, follow-up durations, and baseline Lp(a). The Lp(a) reductions correlated modestly with LDL-C (β = 0.28; 95% CI 0.07-0.49) and apolipoprotein B (apoB) (β = 0.33; 95% CI 0.03-0.63). Concomitant reductions in LDL-C, apoB, and major adverse cardiovascular events were supported by high and moderate certainty evidence. Safety was favorable, with injection-site reactions being the most common adverse event. Sensitivity analyses confirmed robustness of findings after accounting for overlapping trials. The PCSK9 inhibitors, particularly evolocumab 140 mg every 2 weeks, significantly lower Lp(a) alongside LDL-C and apoB. These findings highlight the consistent Lp(a)-lowering effect of PCSK9 inhibitors. However, the observed cardiovascular benefits are largely attributable to concomitant LDL-C reduction, and the incremental contribution of Lp(a) lowering remains uncertain. Confirmation from outcome trials specifically designed to target Lp(a) is required. PROSPERO CRD420251048597. Show less

Children's reading time at home plays a critical role in their reading development. However, existing measures of reading time, based on self-reports, are often biased. Logged data from mobile apps may offer a more reliable alternative, as shown in studies examining screen time in digital media use. This study compared logged and self-reported measures of reading time and examined their associations with reading skills in French primary school children. One hundred and nine children from Grade 1 to Grade 5 and their parents participated. Parents completed a retrospective questionnaire estimating weekly reading time (self-reported measure). They then used a mobile application to record their child's reading activities in real time over a 14-day period (logged measure). All children were assessed on their reading fluency. The self-reported measure yielded significantly higher reading time estimates (M = 6.26 hours/week) than the logged measure (M = 2.11 hours/week), with a moderate correlation between the two (r = .45). Crucially, the logged measure showed stronger predictive validity for reading fluency (r = .39) than the self-reported measure (r = .25). Regression analyses confirmed that when both measures were included simultaneously, only the logged reading time remained a significant predictor of reading performance. These findings suggest that logged measures obtained via ambulatory assessment (here, using a mobile app) provide more accurate estimates of reading time and superior predictive validity compared to traditional self-reports. This methodology offers promising avenues for future research on reading habits and literacy development. Show less

Genetic variations within the Lipoprotein Lipase (LPL) gene have been shown to influence the risk of cardiometabolic diseases. However, their associations with cardiometabolic disease-related markers remain underexplored in Arab Qatari populations. Hence, we examined the association between a genetic risk score (GRS) based on three LPL single nucleotide polymorphisms (SNPs) and cardiometabolic indicators in a healthy Qatari population. A cross-sectional genetic association study was conducted using data from the Qatar Biobank population-based cohort, involving a sample of metabolically healthy Qatari adults (n = 6,919). The LPL-GRS was computed as the unweighted sum of risk alleles from three LPL SNPs: rs295 (C/A), rs301 (C/T), and rs320 (G/T). Associations between the GRS and metabolic markers were assessed using a generalized linear model, adjusting for age, sex, and body mass index. Individuals with high GRS (>5 risk alleles) showed a significant association with lower fat-free mass index values (β = -0.064, p = 0.029). In addition, a positive association was observed between GRS and fasting insulin levels (β = 0.035, p = 0.016). In addition, high GRS was significantly associated with lower high-density lipoprotein cholesterol (β = -0.025, p = 0.001) and higher triacylglycerol concentrations (β = 0.027, p = 0.0003) and systolic blood pressure (β = 0.007, p = 0.002), respectively. Our study shows that the LPL-GRS is associated with key cardiometabolic risk factors in this self-reported healthy Qatari population. These findings highlight the need for additional research to replicate these findings in independent and ethnically diverse cohorts, as well as the use of longitudinal studies to evaluate the predictive value of the GRS for future metabolic outcomes. Show less

Immune checkpoint blockade (ICB) has improved outcomes for patients with triple-negative breast cancer (TNBC), yet resistance remains widespread and its molecular basis is not fully understood. Through single-cell RNA sequencing (scRNA-seq) of paired pre- and post-treatment tumor samples from patients who failed to achieve pathological complete response (non-pCR) after neoadjuvant PD-1 therapy, we identified a marked upregulation of interleukin-27 receptor subunit alpha (IL27RA) in malignant epithelial cells within residual lesions. Integration with scRNA-seq profiles from an independent cohort of three pCR patients showed that this IL27RA upregulation in malignant epithelium is largely restricted to non-pCR residual tumors, and high IL27RA expression correlated with poor survival in TNBC cohorts. Mechanistically, IL27RA suppresses MHC-I expression by activating the PI3K/AKT pathway-rather than the classical IL-27/STAT axis-thereby impairing CD8⁺ T-cell cytotoxic function. Inhibition of AKT reversed this phenotype and restored antigen-specific killing. In orthotopic tumor models, mimicking systemic loss of Il27ra significantly reduced tumor growth and prolonged survival in immunocompetent mice, with single-cell profiling indicating enhanced intratumoral T-cell and NK-cell effector activity. Collectively, our findings identify an epithelial-intrinsic IL27RA-PI3K/AKT-MHC-I axis as a central driver of immune evasion and ICB resistance in TNBC and support IL27RA as a promising therapeutic target for overcoming immunotherapy resistance. Show less

Canine Cognitive Dysfunction (CCD) is an increasingly prevalent naturally occurring neurodegenerative condition in senescent dogs that share neuropathological and clinical features with human Alzheimer's disease (AD). Metabolic profiling allows for identification of new candidates for AD biomarkers, diagnostics, and therapeutics. Despite its translational potential, plasma metabolomic profiling of dogs with CDD has not been previously characterized. This case-control study analyzed plasma samples from ten client-owned geriatric dogs, including five with severe CCD and five age-matched, clinically healthy controls. Untargeted plasma metabolomics was performed using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Multivariate and univariate statistical analyses identified significant metabolic differences between the groups. Metabolites were considered significant based on a variable importance in projection (VIP) score > 1.5, fold change (FC) > 2.0, and adjusted Fifteen metabolites across seven chemical classes were significantly altered in CCD dogs compared to controls, including glycerophospholipids, steroid derivatives, indoles, and mitochondrial-related compounds. Notably, elevated lysophosphatidic acid (LPA 20:2/0:0) and reduced ubiquinone-2 levels suggest dysregulation in neuroinflammatory and oxidative stress pathways. Cholesterol exhibited the highest FC and VIP scores, further reinforcing its role in AD pathogenesis. Hierarchical clustering and pathway enrichment analyses supported distinct metabolic signatures in CCD that mirror those observed in human AD. This is the first untargeted plasma metabolomic profiling of dogs with CCD, revealing systemic metabolic disturbances that align with AD pathophysiology. Data was collected from senescent community-dwelling companion dogs, which enhances the study's ecological and translational relevance. It supports the utility of CCD as an AD model and highlight candidate plasma biomarkers that warrant further investigation. Future longitudinal studies integrating metabolomics with neuroimaging, histopathology, and behavioral assessments are required to validate these findings and contribute to AD biomarker discovery and therapeutic development. Show less

In the present study, a systematic revision in the Medline was conducted to determine the somatic mutation in gangliogliomas. A Medline search for relevant publications up to October 2024 using the key phrase "ganglioglioma mutation" led to the retrieval of 297 studies. This corpus provided the basis for the present review. The records without abstract or descriptions of somatic mutations were excluded. Only records in the English language were considered. A total of 43 papers were evaluated, reporting a total of 1360 cases of ganglioglioma. Among them, 528 cases presented mutations in 6 genes: BRAF BRAF Show less

In the tumor microenvironment, hypoxia and stromal interactions contribute to enhanced malignant behavior in cancer cells. This study aimed to assess whether pancreatic cancer cells with higher malignancy display stronger responses to hypoxia and stromal cells than their less malignant parental cells, and evaluated the underlying mechanisms, focusing on lysophosphatidic acid (LPA) receptor signaling linked to the acquisition of malignant traits. Highly invasive PANC-M10 cells, derived from the parental pancreatic cancer PANC-1 cells, were cultured at 1% O Show less

24-h activity encompasses four categories: light-intensity physical activity (LPA), moderate-to-vigorous-intensity physical activity (MVPA), sedentary behavior (SB), and sleep (SP). This study aims to investigate the effects of different physical activity components on executive function in older adults with chronic diseases and to examine substitution effects among activity components. The findings provide scientific evidence to inform physical activity interventions for improving executive function in older adults with chronic diseases. A total of 105 older adults (72.64 ± 6.82 years) were recruited. Following questionnaire screening, 75 older adults with chronic diseases were ultimately included. Accelerometers objectively measured participants' daily SP, SB, LPA, and MVPA. Executive function was objectively assessed using the Stroop task, N-back task, and More-odd-shifting task. Component linear regression equation assessed the relationship between different activities and executive function in older adults with chronic diseases. The dose-response effects of "one-for-one" substitutions between different activity behaviors were explored. Component linear regression results showed that SB positively correlated with inhibitory control ( SP and MVPA significantly improve inhibitory control in older adults with chronic diseases, while LPA significantly enhances their working memory. It is recommended that older adults with chronic diseases adjust their daily time structure by increasing diverse physical activities, ensuring adequate sleep duration, and reducing sedentary behavior to improve executive function. Show less

We recently demonstrated the utility of the 'TB Concentration & Transport' kit for bio-safe, ambient-temperature transport of dried sputum samples on Trans-Filter, along with the 'TB DNA Extraction' kit for efficient DNA extraction from Trans-Filter for use in the Line Probe Assay (LPA) for diagnosing drug-resistant tuberculosis (TB). The present study aimed to develop and evaluate a new 'Quick TB DNA Extraction' kit ('Quick DNA' kit) for rapid DNA isolation from Trans-Filter samples and assess its compatibility with LPA for the detection of multidrug-resistant TB (MDR-TB). Consecutive presumptive TB/MDR-TB/XDR-TB patients (n = 1823) were screened using LED-FM and/or TBDetect microscopy at 2 Designated Microscopy Centres associated with the National Institute of Tuberculosis and Respiratory Diseases (NITRD), New Delhi. Smear-positive samples (n = 235) were processed in duplicate using the 'TB Concentration and Transport' kit. Dried sputum on bio-safe Trans-Filters was transported at ambient temperature, along with sputum samples, in a 3-layer packing in cooling conditions to NITRD Hospital (a National Reference Laboratory). DNA was extracted from Trans-Filters using 'Quick DNA' kit and the 'TB DNA Extraction' kit, and from sputum using Hain's GenoLyse® DNA Extraction kit for first-line LPA for MDR-TB detection. Quick Kit-LPA and Kit-LPA (LPA with DNA extracted from Trans-Filter using 'Quick DNA' kit and 'TB DNA Extraction' kit, respectively) showed similar sensitivity of 88.9% (95% CI: 65.3-98.6) and 88.5% (95% CI: 69.9-97.5) and specificity of 100% (95% CI: 98.2-100) and 99.5% (95% CI: 97.3-99.9) for rifampicin and isoniazid resistance detection, respectively against Direct-LPA (LPA with DNA extracted from sputum samples using GenoLyse kit). User feedback obtained from laboratory technicians corroborated that the one-step 'Quick DNA' kit procedure was rapid (5 minutes), easy to perform, seamlessly integrated with LPA testing, and was suitable as a replacement for Kit-LPA or Direct-LPA. The gap between drug-resistant TB detection and treatment initiation can be narrowed through Universal-Drug Susceptibility Testing by implementing (i) bio-safe and ambient temperature transport of sputum from primary healthcare centres to central laboratories, and (ii) by using Quick Kit-LPA over Direct-LPA in patients residing in remote areas. Show less

Between 1920 and 1950, cardiovascular disease (CVD) underwent a profound epidemiological shift, rising from a relatively rare and infrequently diagnosed condition to become the leading cause of death in industrialized nations. This epidemic coincided with a series of changes in the food supply, including the expanded use of refined carbohydrates, industrial seed and vegetable oils, and trans fatty acids. In response, the "Diet-Heart Hypothesis" emerged, dominated by Ancel Keys' lipid theory, which focused scientific and public health attention on saturated fat and cholesterol as the primary causes of CVD. This paradigm profoundly shaped dietary guidelines for decades, yet the sugar industry's documented influence on nutritional research during this period raises questions about how economic interests may have deflected scrutiny from other dietary factors. This review critically examines the evolution of cardiovascular risk assessment, exploring both the historical context of CVD emergence and the contemporary evidence supporting biomarkers that may be better at predicting risk than traditional cholesterol-focused approaches. Significant evidence reveals limitations in the lipid hypothesis, which oversimplified cardiovascular risk by demonizing total and LDL cholesterol. Research now demonstrates that apolipoprotein B and non‑HDL cholesterol more accurately reflect atherogenic lipoprotein burden than LDL cholesterol alone, while the triglyceride‑to‑HDL cholesterol ratio is a useful marker of insulin resistance and metabolic dysfunction. Lipoprotein(a), an independent genetic risk factor, accounts for a substantial proportion of cardiovascular events previously attributed to other causes. Furthermore, inflammatory markers like high-sensitivity C-reactive protein add prognostic value beyond traditional lipid panels. Perhaps most importantly, the historical dominance of saturated fat as a dietary "villain" is challenged by contemporary meta-analyses showing no significant association with CVD, while the roles of refined carbohydrates, industrial trans fats, and excess omega-6 fatty acids, such as those in soybean oil, warrant greater scrutiny. Contemporary cardiovascular risk assessment must move beyond LDL cholesterol-centric approaches to incorporate comprehensive metabolic and inflammatory markers. Apolipoprotein B, lipoprotein(a), triglyceride-to-HDL ratio, and high-sensitivity C-reactive protein provide more nuanced risk stratification, while dietary recommendations should acknowledge that industrial food processing, refined carbohydrates, and specific fatty acid compositions may pose greater cardiovascular threats than naturally occurring saturated fats. This paradigm shift demands updated clinical guidelines that reflect current scientific understanding rather than historical assumptions, potentially revolutionizing both prevention and treatment strategies for CVD. Show less

RNA-based therapies have emerged as a transformative approach in the management of hypercholesterolemia and coronary artery disease by directly targeting molecular pathways involved in lipid regulation. These treatments focus on silencing key genes such as PCSK9, ANGPTL3, ApoB, and Lp(a), achieving substantial reductions in low-density lipoprotein cholesterol (LDL-C), triglycerides, and other atherogenic lipoproteins. Small interfering RNA (siRNA) and antisense oligonucleotides (ASOs) provide highly specific post-transcriptional gene suppression, while advances in chemical stabilization and GalNAc conjugation have enhanced hepatocyte delivery and prolonged therapeutic action. Approved agents such as inclisiran demonstrate sustained LDL-C reductions of approximately 50% with only two to three injections annually, improving adherence and offering an alternative for patients intolerant to statins or unable to reach lipid targets with conventional therapy. Pelacarsen and other emerging antisense therapies show promise for reducing lipoprotein(a), an independent cardiovascular risk factor, while siRNAs targeting ANGPTL3 offer prolonged lipid-lowering effects beyond those achieved with monoclonal antibodies. Despite these advantages, challenges remain. Hepatic safety concerns have halted the development of some agents, such as vupanorsen, and long-term cardiovascular outcome data for several therapies, including inclisiran, are still in development. Cost and accessibility also limit broad adoption, emphasizing the need for cost-effective strategies and long-term surveillance. Nevertheless, current evidence supports the integration of RNA-based therapies into modern lipid-lowering algorithms, particularly for high-risk patients, while ongoing research continues to refine delivery systems, enhance safety, and expand therapeutic indications. Show less

Spinocerebellar ataxia type 3 (SCA3) is one of the most common dominantly inherited ataxias worldwide. Despite research advances, no approved disease-modifying treatment exists, and management focuses on symptom alleviation and functional capacity maximization. Symptomatic treatment guidelines are scarce, leaving decisions to physicians' discretion. The lack of studies on SCA3 symptom management hinders therapy standardization. The aim of this study was to investigate medication-usage patterns among SCA3 mutation carriers and controls included in the multicentric European Spinocerebellar Ataxia Type-3/Machado-Joseph Disease Initiative (ESMI) cohort. We conducted a retrospective cross-sectional analysis of the medication taken by ESMI participants enrolled in the study between 2016 and 2023. Medication being used at the most recent follow-up visit available was categorized according to the Anatomical Therapeutic Chemical system. Comparisons between groups were performed using nonparametric tests for continuous variables and Fisher's exact test for categorical variables. In addition, a retrospective longitudinal analysis was conducted to study the impact of medication subclasses on disease progression, using linear mixed-effects models adjusted for relevant covariates. A total of 474 participants were included, comprising 344 SCA3 mutation carriers and 130 controls. Compared with controls, SCA3 subjects took more vitamins, mineral supplements, muscle relaxants, and medications targeting the nervous system. Psychoanaleptics and vitamins were introduced early in the disease course, whereas most other subclasses were initiated in mid-to-late stages, coinciding with the onset of neurological symptoms. Substantial disparities in medication usage were observed across the study centers. None of the medication subclasses commonly used by patients with SCA3 showed a significant impact on disease progression. This is the first study to explore medication usage patterns in SCA3 mutation carriers. Our study provides a comprehensive overview of the medications administered in SCA3 and underscores the importance of collaborative efforts toward achieving standardized clinical practices in the management of this disease. Show less

In recent years, non-traditional lipid indices have emerged as significant predictors for cardiovascular events following emergency percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). However, the relationship of residual lipoprotein-cholesterol (RLP-C) and atherogenic index of plasma (AIP) with in-hospital outcomes, especially their predictive value for major adverse cardiovascular and cerebrovascular events (MACCEs) after PCI in STEMI patients, remains underexplored and warrants further investigation. This retrospective cohort study included 526 STEMI patients who underwent emergency PCI between January 2023 and August 2024. We collected baseline demographic, clinical, and laboratory data. RLP-C and AIP were calculated from lipid profiles obtained before PCI. Independent predictors of in-hospital MACCEs were identified using multivariate logistic regression, and model discrimination was evaluated using receiver operating characteristic (ROC) curve analysis. Among 526 STEMI patients receiving PCI, 92 (17.49%) developed in-hospital MACCEs. Multivariate analysis identified RLP-C (OR = 3.97, 95%CI: 1.71–9.21; RLP-C and AIP are independent predictors of in-hospital MACCEs following PCI in STEMI patients. Combined assessment of these indices improves risk stratification and may facilitate early targeted interventions to improve outcomes. The online version contains supplementary material available at 10.1186/s12872-026-05555-9. Show less

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths. Immune checkpoint inhibitors (ICIs) of programmed death-1 (PD-1)/programmed death ligand-1 signaling induce tumor regression in some patients with NSCLC, but most patients with NSCLC exhibit resistance to ICIs therapy. NSCLC shapes the potent tumor immunosuppressive microenvironment (TIME) that underlies tumor immune tolerance and acquired resistance. Therefore, elucidating the cellular and molecular mechanisms by which NSCLC establishes and sustains the TIME is essential for developing novel strategies to overcome immune resistance and enhance the clinical benefit of ICIs. The correlation between sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) expression and ICIs was analyzed via immunohistochemistry. Cell migration assay was performed to assess the effect of SAMHD1 on macrophage recruitment. Multicolor flow cytometry was performed to analyze the effect of SAMHD1 knockdown on the tumor microenvironment. SAMHD1 regulation of the dual specificity phosphatase 6-extracellular regulated protein kinases 1/2 (DUSP6-ERK1/2) pathway was verified by RNA sequencing and western blotting. Here, we identify the SAMHD1 as a potential therapeutic target and a major determinant of poor response to ICIs in patients with NSCLC. Tumors with high SAMHD1 expression show resistance to anti-PD-1 antibody (αPD-1) treatment, whereas tumors with low SAMHD1 expression are highly sensitive. SAMHD1-dependent resistance to αPD-1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, SAMHD1 regulates the expression of macrophage-associated chemokines by influencing the activation of the DUSP6-ERK1/2 pathway, which contributes to TAMs aggregation within NSCLC tumors to shape an immunosuppressive microenvironment. The HIV accessory protein viral protein-x (VPX) specifically degrades SAMHD1 to promote HIV replication. Similarly, the vpx-engineered oncolytic adenovirus (oAd-vpx) targets SAMDH1 degradation to enhance oncolytic adenovirus replication and weaken the hostile immune microenvironment shaped by TAMs, thereby triggering a CD8+T-cell-dependent antitumor immune response. The combination of oAd-vpx and αPD-1 inhibits tumor growth and enhances sensitivity to ICIs in both mouse and human NSCLC. This research identifies a key mechanism of SAMHD1-driven immunosuppression and highlights its important role in oncolytic adenovirus therapy. This study provides a theoretical basis for targeting SAMHD1 as a drug therapy strategy in patients with NSCLC. Show less

This study aims to investigate the effect of exosomes derived from olfactory mucosa mesenchymal stem cells (OM-MSCs-Exo) on microglial polarization and its potential therapeutic role in Alzheimer's disease (AD). OM-MSCs-Exo were isolated and purified from the mice olfactory mucosa, followed by phenotypic characterization. Proteins transferred by OM-MSCs-Exo were screened using proteomic analysis. The AD model was established in microglial cells and mice with Aβ Show less

Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) is critical for transporting lipoprotein lipase (LPL) to the capillary lumen, where LPL breaks down triglycerides in triglyceride-rich lipoproteins. We herein report a 12-year-old Chinese girl who presented with severe hypertriglyceridemia and a recent diagnosis of systemic lupus erythematosus (SLE). She was first noted to have severe hypertriglyceridemia at 8.5 years old, complicated by three episodes of acute pancreatitis within 2 years. Between these episodes, her plasma triglycerides remained elevated, but at lower levels. Next-generation sequencing for primary hypertriglyceridemia yielded no significant findings. Investigations for secondary causes, to include fasting glucose, HbA1c, and thyroid function testing, were unrevealing. Given the fluctuating triglyceride levels and negative genetic testing for primary hypertriglyceridemia in the background of SLE, autoimmune hypertriglyceridemia was suspected. The diagnosis of GPIHBP1 autoantibody syndrome was confirmed by an elevated GPIHBP1 autoantibody titer and a low LPL mass in her serum. Her SLE was well controlled with immunosuppressants and belimumab. Fenofibrate and omega-3 fatty acids, which were initially prescribed for her hypertriglyceridemia, were later discontinued. The GPIHBP1 autoantibody and LPL mass normalized 2 years after diagnosis. This case illustrates hypertriglyceridemia caused by a rare disease entity associated with autoantibodies against the GPIHBP1 protein. This entity is worth considering after excluding genetic and common secondary causes of hypertriglyceridemia, particularly in a patient with a history of autoimmune disease. Show less

Imperfect first-trimester screening for hypertensive disorders of pregnancy (HDP) means many high-risk women miss the window for preventive aspirin, and the biological heterogeneity of HDPs is overlooked. This study aimed to leverage first-trimester serum proteomics to create a more precise tool for predicting preeclampsia (PE) and differentiating it from other HDPs. A prospective nested case-control study ( Show less

Gene editing technologies have revolutionized therapeutic development, offering potentially curative and preventative strategies for cardiovascular disease (CVD), which remains a leading global cause of morbidity and mortality. This review provides an introduction to the state-of-the-art gene editing tools-including ZFNs, TALENs, CRISPR/Cas9 systems, base editors, and prime editors-and evaluates their application in lipid metabolic pathways central to CVD pathogenesis. Emphasis is placed on targets such as Show less