Search Results (2,412)

The mechanism of kidney injury associated with apolipoprotein L1 (APOL1) risk variants has remained elusive. Complicating this issue is the broad clinical spectrum of APOL1 kidney disease, which has engendered speculation that this reflects multiple mechanisms of kidney injury. APOL1 kidney disease can be rapid in onset with heavy proteinuria, associated with viral infections and categorized pathologically as collapsing focal segmental glomerulosclerosis. Alternatively, APOL1 kidney disease also may present as an insidious, slowly progressive disease, with less proteinuria but losses in glomerular filtration rate and with varied pathology. In addition to APOL1 kidney disease, APOL1 risk variants are also associated with preeclampsia and other conditions related to placental insufficiency. The outcome of these APOL1-associated pregnancy complications frequently results in prematurity and low birth weight, both of which are known risk factors for hypertension and kidney disease later in life due to reduced nephron endowment. The significance of APOL1 risk variants on pregnancy complications that predispose to kidney disease should not be overlooked as a central mechanism of APOL1 kidney disease, especially the insidious forms, which are difficult to distinguish from the spectrum of kidney disease attributable to prematurity and low birth weight. If low nephron endowment is a causal mechanism behind some forms of APOL1 kidney disease, this may have an impact on clinical trials evaluating drugs directly inhibiting APOL1, since in these instances, ongoing APOL1 expression may not be driving podocyte loss and progressive kidney dysfunction. Full article

Small and medium-sized enterprises (SMEs) often face severe resource constraints and operational fragility during crises. However, little is known about how managerial resilience (MR) translates into performance through time-related psychological resources and innovation—two capabilities that are both scarce and critical under such conditions. Drawing on Temporal Motivation Theory (TMT), this study develops and tests a dual-mediation model in which employee temporal psychological capital (TPC) and employee innovative behavior (EIB) transmit the effects of MR on performance. As a core methodological innovation, we adopt a multi-method analytical strategy to provide robust and complementary evidence rather than a hierarchy of results: Partial Least Squares Structural Equation Modeling (PLS-SEM) is used to examine sufficiency-based causal pathways and quantify the mediating mechanisms; Support Vector Machine (SVM) classification offers a non-parametric predictive validation of how MR and its mediators distinguish high- and low-performance cases; and Necessary Condition Analysis (NCA) identifies non-compensatory conditions that must be present for high performance to occur. These three methods address different research questions—sufficiency, classification robustness, and necessity—therefore serving as parallel, equally important components of the analysis. A total of 455 SME managers and employees were surveyed, and results show that MR significantly enhances all three dimensions of TPC (temporal control, temporal fit, time pressure resilience) and EIB (idea generation, idea promotion, idea realization), which in turn improve employee performance. SVM classification confirms that high MR, strong TPC, and active innovation align with high performance, while NCA reveals temporal control, idea generation, and idea realization as necessary bottleneck conditions. By integrating sufficiency–necessity logic with predictive classification, our findings suggest that SMEs should prioritize leadership resilience training to strengthen managers’ adaptive capacity, while simultaneously implementing time management interventions—such as temporal control workshops, workload balancing, and innovation pipeline support—to enhance employees’ ability to align tasks with organizational timelines, execute ideas effectively, and sustain performance during crises. Full article

Unsafe behavior among air traffic controllers is a significant causal factor in civil aviation safety incidents. To explore the risks and pathways associated with controller-induced aviation accidents, this study develops an analytical model of controller unsafe behavior based on association rules and fault tree Bayesian networks. First, the Human Factors Analysis and Classification System (HFACS) was applied to identify and categorize aviation incident reports attributed to controller errors. Next, association rule algorithms were employed to uncover potential associations between controller unsafe behaviors and related risk factors, and a fault tree Bayesian network (FT-BN) model of controller unsafe behaviors was constructed based on these associations. The results revealed that the most likely unsafe behaviors were: improper allocation of aircraft spacing (30.5%), failure to take necessary intervention measures (28.4%), and improper transfer of control (27.8%). Backward analysis of the FT-BN indicated that improper allocation of aircraft spacing was most likely triggered by failure to provide adequate controller training, failure to take necessary intervention measures was most often caused by forgotten information, and improper transfer of control was most frequently associated with controller fatigue and failure to put risk management efforts in place. This study provides an important framework for the analysis and evaluation of controller behavior management and offers key insights for improving air traffic safety. Full article

This study examines how employees’ psychological capital relates to workplace stress and mobbing (also known as workplace bullying) across three European countries. Stress has become an increasingly dominant issue globally since the second half of the 20th century, moving from clinical contexts into public awareness. It is now recognized as a significant health risk factor, particularly in work environments. While positive forms of stress (eustress) can enhance performance, chronic workplace stress is linked to serious mental and physical health problems. This study investigates the relationship between psychological capital (PsyCap), workplace stress, and mobbing among employees in Germany, Austria, and Hungary. Based on a cross-sectional survey (N = 89), the research applied validated instruments (PCQ, PSS-10, COPSOQ II) to measure PsyCap, perceived workplace stress, and experiences of mobbing. Results show a high average PsyCap level (M = 4.64, SD = 0.70) and a moderate perceived workplace stress level (M = 2.73, SD = 0.62) across the sample. A strong negative correlation was identified between PsyCap and workplace stress (r = −0.573, p < 0.001), while a moderate positive correlation was found between workplace stress and mobbing experiences (r = 0.323, p = 0.002). Although PsyCap moderated stress levels, it did not significantly moderate the relationship between mobbing and perceived stress. These findings emphasize the role of PsyCap in reducing workplace stress and underline the necessity of organizational interventions in promoting psychological resilience and mobbing prevention. The results also indicate a need to further examine the causal relationship between mobbing, stress, and PsyCap. Full article

We recently developed a mechanical acupuncture instrument (MAI) that applies mechanical stimulation to acupuncture points in effectively treating hypertension and addiction in animal models. However, its analgesic effect on inflammatory pain remains unclear. Here, we aimed to determine the optimal duration of MAI treatment at any given acupuncture point to improve analgesic effects. Adult male ICR mice (20–25 g, 6 weeks old, n = 6 per group) were used to evaluate whether MAI administration or TRPV1 (transient receptor potential vanilloid 1) inhibition had analgesic effects. Then, we investigated whether it affected TRPV1 expression and glial cells in the spinal cord of mice. The capsaicin test was used to identify the most effective acupoints and optimal treatment times for MAI. Additionally, we induced inflammatory pain in mice by administering a 2% carrageenan via intraplantar injection. To assess the analgesic effects of MAI treatment and TRPV1 inhibition, we evaluated pain-related behavior using von Frey filaments and a thermal stimulator applied to the hind paw. MAI treatment significantly suppressed pain-related behaviors. In particular, paw-licking duration was markedly reduced in the group treated with MAI for 60 s at ST36 compared to the capsaicin-treated group (p < 0.05), suggesting a robust analgesic effect. Additionally, MAI and capsazepine administration significantly attenuated carrageenan-induced mechanical allodynia and thermal hyperalgesia compared to the carrageenan-only group (p < 0.05 to p < 0.001). Additionally, MAI treatment and capsazepine administration effectively suppressed the carrageenan-induced upregulation of TRPV1 and glial cells in the spinal cord. In conclusion, our findings show that MAI administration at ST36 significantly alleviated inflammatory pain and was associated with downregulation of TRPV1 expression and microglial activation in the spinal cord. The present findings suggest that TRPV1 signaling is involved in the analgesic effects of mechanical acupuncture; however, a direct causal relationship has yet to be established. Full article

Alpha-1 antitrypsin deficiency (AATD) represents a paradigmatic genetic disorder with well-characterized hepatic manifestations but relatively underexplored pulmonary implications. While liver involvement has been extensively reviewed, the underlying mechanisms of lung disease progression remain poorly understood, particularly regarding immunological pathways and inflammatory processes. The pathophysiology involves defective alpha-1 antitrypsin (AAT) production, including AAT variants that induce neutrophil elastase activity, causing progressive alveolar destruction and sustained inflammation, leading to emphysema, as one of the main components of chronic obstructive pulmonary disease (COPD). AATD and smoking represent major risk factors for COPD, the third leading cause of death worldwide at present. In AATD patients, neutrophils, which constitute the majority of circulating leukocytes, become dysregulated. Under normal conditions, cells perform essential functions, including phagocytosis and neutrophil extracellular trap formation (NETosis); in AATD, however, they accumulate excessively in alveolar spaces due to impaired elastase control. The accumulation of Z-AAT polymers within epithelial cells creates a pathological cycle, acting as chemoattractants that sustain pro-inflammatory responses and contribute to chronic obstructive pulmonary disease development. In addition, monocytes, representing a smaller fraction of leukocytes, migrate to inflammatory sites and differentiate into macrophages while secreting AAT with anti-inflammatory properties. However, in PiZZ patients, this protective mechanism fails, as polymer accumulation within cells reduces both AAT secretion and the number of protective human leukocyte antigen(HLA)-DR-monocyte subsets. In particular, macrophages demonstrate remarkable plasticity, switching between pro-inflammatory M1 (classically activated macrophages) and tissue-repairing M2 (alternatively activated macrophages) phenotypes based on environmental cues. In AATD, this adaptive capability becomes compromised due to intracellular polymer accumulation, leading to impaired phagocytic function and dysregulated cytokine production and ultimately perpetuating chronic inflammation and progressive tissue damage. Recent advances in induced pluripotent stem cell (iPSC) technology have facilitated alveolar epithelial cell (AEC) generation, in addition to the correction of AATD mutations through gene editing systems. Despite the limitations of AAT correction, iPSC-derived organoid models harboring AATD mutations can deliver important insights into disease pathophysiology, while gene editing approaches help demonstrate causality between specific mutations and observed phenotypes. Therefore, in this review, we investigated recent studies that can serve as tools for gene editing and drug development based on recently developed iPSC-related technologies to understand the pathogenesis of AATD. Full article

Background/Objectives: Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by lung scarring, impaired function, and high mortality. Effective therapies to reverse fibrosis are lacking. This study aims to uncover the molecular mechanisms of IPF, explore diagnostic biomarkers, and identify therapeutic targets. Methods: Multi-omics data were integrated to identify biomarkers with causal associations to IPF using Mendelian randomization and transcriptomic analysis. Machine learning was employed to construct a diagnostic model, and single-cell transcriptomic analysis determined gene expression patterns in fibrotic lung tissue. Results: Seven core genes (GREM1, UGT1A6, CDH2, TDO2, HS3ST1, ADGRF5, and MPO) were identified, showing strong diagnostic potential (AUC = 0.987, 95% CI: 0.972–0.987). These genes exhibited distinct distribution patterns in fibroblasts, endothelial cells, epithelial cells, macrophages, and dendritic cells. Conclusions: This study highlights key genes driving IPF, involved in pathways related to metabolism, immunity, and inflammation. However, their utility as fluid-based biomarkers remains unproven and requires protein-level validation in prospective cohorts. By integrating genomic, immunological, and cellular insights, it provides a framework for targeted therapies and advances mechanism-based precision medicine for IPF. Full article

Stream temperatures are expected to increase with warming air temperatures, yet the extent and aquatic health impacts vary significantly across heterogeneous landscapes. This study was conducted in a 3360-ha multi-land-use watershed in the Pacific Northwest region of the USA to assess and compare the driving factors for stream temperature heating, cooling, and cool-water refugia along a 12-km mainstem stream longitudinal profile. Study objectives were to (1) determine yearlong stream temperature variability along the entire stream longitudinal profile, and (2) assess stream-environment relationships influencing stream temperature dynamics across forest, agriculture, and urban landscapes within the watershed. Stream and riparian air temperatures, solar radiation, shade, and related stream-riparian characteristics were measured over six years at 21 stations to determine changes, along the longitudinal profile, of thermal sensitivity, maximum and minimum stream temperatures, and correlation between solar radiation and temperature increases, and potential causal factors associated with these changes. Solar radiation was a primary heating factor for an exposed agricultural land use reach with 57% effective shade, while southern stream aspects and incoming tributary conditions were primary factors for forested reaches with greater than 84% effective shade. Potential primary cooling factors were streambank height, groundwater inflows, and hyporheic exchange in an urban reach with moderate effective shade (79%) and forest riparian width (16 m). Combining watershed-scale analysis with on-site stream-environmental data collection helps assess primary temperature heating factors, such as solar radiation and shade, and potential cooling factors, such as groundwater and cool tributary inflows, as conditions change along the longitudinal profile. Full article

Background/Objectives: Mental disorders are a growing global concern, with depression being among the most prevalent. Portugal ranks second in antidepressant consumption within the OECD, following a threefold increase between 2000 and 2020. In inland regions such as Beira Interior, reduced healthcare services and distance from major hospitals further complicate access to care. This study analysed 142 patients from Beira Interior undergoing antidepressant therapy to characterise their demographic and clinical profile and to assess associations with adverse effects. Methods: A cross-sectional survey collected demographic data, clinical diagnoses, prescribed antidepressants, concomitant medications, and reported adverse effects. Both descriptive and inferential statistical analyses were performed. Results: Most participants were female (81.0%), with a mean age of 57.8 years. Major depression was the most common diagnosis (76.1%). Selective serotonin reuptake inhibitors (47.4%) and trazodone (27.8%) were the most prescribed agents. Treatment had lasted one to five years in 59.9% of cases. Concomitant use of benzodiazepines (76.8%) and antipsychotics (48.6%) was frequent. Reported adverse effects included anticholinergic symptoms (38.7%) and confusion/agitation (26.8%). Women were more likely to use serotonin modulators, while patients >64 years had higher odds of using tetracyclic/unicyclic antidepressants, serotonin modulators, and multiple antidepressants. These classes were significantly associated with increased adverse effects. Conclusions: The findings reveal important risks related to polypragmasia and adverse reactions, underscoring the need for individualised prescribing, rigorous monitoring, and strict adherence to guidelines. Larger, stratified, and longitudinal studies are needed to clarify causality and optimise treatment outcomes. Full article

Proton pump inhibitors (PPIs) are among the most prescribed drugs worldwide owing to their proven efficacy in symptom control and mucosal healing for acid-related disorders including gastroesophageal reflux disease (GORD), peptic ulcer disease, Helicobacter pylori eradication, functional dyspepsia, and gastroprotection in high-risk patients. However, long-term use beyond approved indications is increasingly common and has raised safety concerns. Observational studies link chronic PPI use to a myriad of adverse outcomes such as enteric infections (e.g., Clostridioides difficile), nutrient deficiencies (magnesium, vitamin B12), osteoporotic fractures, chronic kidney disease, dementia, and gastric and colorectal cancer. While causality is not always established, these associations warrant cautious risk–benefit assessment in patients receiving prolonged therapy. Current guidelines advocate periodic review of ongoing PPI use and emphasise deprescribing where appropriate. Strategies include dose reduction, on-demand or intermittent use, and switching to H2-receptor antagonists, particularly in patients with non-erosive reflux disease or functional dyspepsia. Tools from the National Institute for Health and Clinical Excellence, American College of Gastroenterology, and the Canadian Deprescribing Network assist clinicians in identifying candidates for tapering or discontinuation. This narrative review focuses on the concept of “PPI stewardship” by providing an evidence-based overview of PPI indications, risks, and deprescribing strategies to promote appropriate, safer, and patient-centred use of acid-suppressive therapy. Full article

Background: Chemokines play a pivotal role in the progression of osteoarthritis (OA), but their exact mechanisms remain unclear. This study aimed to identify potential chemokine-associated biomarkers and investigate their causal relationships with OA. Methods: Transcriptome and genome-wide association study (GWAS) data were obtained from public databases, while chemokine-related genes (CRGs) were sourced from the literature. Initially, CRGs were expanded, followed by Mendelian randomization (MR) analysis, differential expression analysis, machine learning, and receiver operating characteristic (ROC) curve plotting to identify potential biomarkers. The causal relationships between these biomarkers and OA, as well as their biological functions, were further explored. Results: Fourteen candidate genes were identified for machine learning analysis, with DDIT3, CEBPB, CX3CR1, and ARHGAP25 emerging as feature genes. CEBPB and CX3CR1, which exhibited AUCs > 0.7 in the GSE55235 and GSE55457 datasets, were selected as potential biomarkers. Notably, CEBPB expression was lower, while CX3CR1 expression was elevated in the case group. Furthermore, both genes were co-enriched in spliceosome, lysosome, and cell adhesion molecule pathways. MR analysis confirmed that CEBPB and CX3CR1 were causally linked to OA and acted as protective factors (IVW model for CEBPB: OR = 0.9051, p = 0.0001; IVW model for CX3CR1: OR = 0.8141, p = 0.0282). Conclusions: CEBPB and CX3CR1 were identified as potential chemokine-related biomarkers, offering insights into OA and suggesting new avenues for further investigation. Full article

Background: Although several epidemiological studies have suggested a potential association between infections and Parkinson’s disease (PD), relatively few have specifically examined the relationship between upper respiratory tract infections (URIs) and PD, apart from coronavirus disease 2019 (COVID-19). Objectives: We investigated whether a history of URI was associated with the diagnosis of PD among Korean individuals aged ≥40 years, using data from the Korean National Health Insurance Service–Health Screening Cohort. Methods: A total of 5844 patients newly diagnosed with PD were identified and matched with 23,376 control participants at a 1:4 ratio based on age, sex, income, and geographical region. Conditional logistic regression analyses were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for PD, adjusting for potential confounders including smoking, alcohol consumption, body mass index, blood pressure, comorbidity scores, blood glucose, and serum cholesterol levels. Results: Overall, no significant association was found between a history of URI and PD when considering a two-year exposure window. However, in the one-year window analysis, individuals with a history of URI had a modestly reduced odds of PD (≥1, ≥2, or ≥3 episodes: (adjusted OR: 0.93, 95% CI: 0.88–0.97, aOR: 0.91, 95% CI: 0.87–0.96 and aOR: 0.92, 95% CI: 0.87–0.98, respectively). Subgroup analyses revealed that the inverse association was more pronounced among women, older adults (≥65 years), and those with higher comorbidity scores. No clear dose–response trend was observed across increasing frequencies of URI diagnoses. Conclusions: Our findings suggest that the apparent protective association between recent URI history and PD is unlikely to be causal and may instead reflect confounding by medication use or reverse causation related to the prodromal phase of PD. These results should therefore be interpreted with caution and regarded as hypothesis-generating. Further prospective studies incorporating detailed prescription data and long-term follow-up are warranted to clarify the role of infections and anti-inflammatory medications in the pathogenesis of PD. Full article

As rural populations age at an accelerating pace, the role of public spaces in enhancing the quality of life and promoting social engagement among older adults has become increasingly important. However, a significant cognitive gap persists between the actual needs of elderly users and the intentions of designers, often resulting in suboptimal design outcomes and underutilized spaces. This study centers on the concept of user–designer cognitive synergy, aiming to establish a systematic framework to bridge this cognitive divide and improve the design quality of age-friendly rural public spaces. Employing Grounded Theory, the FKANO model, and the DEMATEL method, this study systematically elicited user needs, classified their attributes, and mapped causal relations to determine priority drivers. Applied in a representative rural case, the framework identified Environmental and Operations Management and Spatial Accessibility as the most critical needs, while Smart-Friendliness and Safety Organization were also shown to play significant roles. These findings directly informed targeted spatial strategies such as barrier-free circulation, robust nighttime safety systems, intergenerational hubs, and an operations backbone. Post-occupancy evaluation confirmed high satisfaction across safety, accessibility, functionality, social participation, and environmental comfort. The results demonstrate the framework’s effectiveness in translating complex needs into actionable design strategies, offering both theoretical insights and practical guidance for age-friendly rural public space development. Full article

Background: Child Development Accounts (CDAs) were introduced in the 1990s as a long-term asset-building policy aimed at supporting families in accumulating assets to achieve life goals for their children, including higher education, homeownership, and long-term economic security. Beyond their financial benefits, CDAs have been theorized to strengthen family relationships and improve children’s well-being by fostering a future-oriented mindset and increasing parental involvement in educational activities. Objective: This study investigates the impact of CDAs on parent–child educational engagement and children’s sense of hope for the future, contributing to the growing body of research on the multidimensional benefits of asset-based policies for children’s development. Methods: Data were drawn from the third wave of the SEED for Oklahoma Kids (SEED OK) study, a rigorous, longitudinal, randomized policy experiment in the United States. The analytic sample comprised 1425 families. Dependent variables were parent–child educational engagement and children’s hope. The independent variable was participation in the SEED OK CDA policy experiment. Baseline sociodemographic variables related to children, mothers, and households were controlled for in the analysis. Multivariate linear regressions and path analysis techniques were employed to assess direct and indirect effects. Results: Participation in CDAs was found to improve parent–child educational interactions and enhance children’s hope significantly in the pre-COVID-19 sample. The study’s rigorous design and consistent implementation allowed for establishing causal relationships and long-term developmental benefits. Conclusions: CDAs offer not only financial advantages but also contribute meaningfully to strengthening family dynamics and promoting positive psychosocial outcomes for children, supporting their inclusion in comprehensive social policy frameworks. Full article

Background: The 21st century is characterized by a significant and ongoing rise in the aging population across Europe. In this context, marital status may act as a relevant social factor influencing health trajectories in later life. This study explores the association between marital status and various health-related outcomes in community-dwelling older adults. Methods: We enrolled 1201 patients ≥ 65 years (median age: 81, interquartile range (IQR): 76–84) attending the Geriatric Outpatient Service at the University Hospital of Cagliari. Each participant underwent a Comprehensive Geriatric Assessment (CGA). Results: Married individuals were significantly less likely to report depressive symptoms (Risk Ratio (RR) = 0.82; 95% Confidence Interval (CI): 0.73 to 0.92; p = 0.0004) and had a 1.26-point reduction in Geriatric Depression Scale (GDS) scores (β = –1.26; 95% CI: −2.03 to −0.50; p = 0.0013). Separate/Single participants exhibited significantly higher Mini-Mental State Examination (MMSE) scores (β = 1.60; 95% CI: 0.19 to 3.01; p = 0.0262). In contrast, Widowed individuals showed significantly poorer cognitive performance (RR = 1.12; 95% CI: 1.02 to 1.23; p = 0.0204), with lower MMSE scores (β = −1.10; 95% CI: −2.08 to 0.12; p = 0.0279). They also had a higher likelihood of depressive symptoms (RR = 1.16; 95% CI: 1.04 to 1.30; p = 0.0072) and a 1.19-point increase in GDS scores (β = 1.19; 95% CI: 0.38 to 1.99; p = 0.0039). Conclusions: Although observational design precludes causal inference, our findings highlight the significance of marital status as a social factor associated with cognitive function and mood in older adults. Integrating this dimension into the CGA may enhance its ability to capture social vulnerabilities in later life. Full article