Paroxysmal sympathetic hyperactivity (PSH) is a devastating complication of traumatic brain injury (TBI), characterized by the simultaneous onset of various manifestations due to sympathetic overactivity. Paradoxical bradycardia, an uncommon manifestation of PSH, is poorly characterized, and there is limited evidence regarding its clinical features, pathophysiological mechanisms and targeted management. A 25-years-old male sustained severe traumatic brain injury in a nighttime motorcycle collision with a parked vehicle and underwent multiple neurosurgical procedures. He developed typical PSH on day 48 post injury, with a Paroxysmal Sympathetic Hyperactivity Assessment Measure (PSH-AM) score of 27. On the 92nd day post-injury, the patient developed persistent resting bradycardia (40-66 beats/min) after cranioplasty, while a reduced maximum heart rate (140-159 beats/min) was noted during PSH episodes. He subsequently experienced an acute PSH episode with severe bradycardia (38-43 beats/min, PSH-AM score of 20). After excluding common predisposing factors, intravenous isoproterenol (initial dose 4 μg/min, titrated to 2 μg/min) was administered in combination with anti-PSH medication regimen, and the patient's clinical symptoms were relieved. The patient was discharged in a stable condition and had no further episodes of bradycardia at the 3-months follow-up. Paradoxical bradycardia represents an atypical clinical phenotype of post-TBI PSH, likely mediated by an atypical Cushing reflex secondary to fluctuating intracranial pressure elevations during PSH exacerbations. Clinically, for TBI patients with unexplained bradycardia, potential primary causes should be actively explored, with particular attention to monitoring dynamic changes in intracranial pressure.
Generative AI is reshaping knowledge work, yet its influence on employee knowledge behavior remains theoretically fragmented. Drawing on the Automation-Augmentation Paradox and Cognitive Appraisal Theory, this study constructs a dual-pathway moderated mediation model to examine how generative AI usage simultaneously affects knowledge sharing and knowledge hiding. We propose that AI usage enhances self-efficacy through the augmentation mechanism, thereby promoting knowledge sharing through the empowerment pathway, while simultaneously heightening job insecurity through the automation mechanism, thereby reinforcing knowledge hiding through the threat pathway. To capture the net behavioral tendency, we introduce Knowledge Behavior Relative Intensity, defined as the difference between knowledge sharing and knowledge hiding scores, as an integrative outcome variable. Furthermore, competitive psychological climate is examined as a moderator that amplifies both pathways. Using survey data from 428 knowledge workers in China, we tested the hypotheses with hierarchical regression and PROCESS bootstrap analyses. Results supported all hypotheses: AI usage positively predicted both knowledge sharing and knowledge hiding, with the former effect substantially stronger. The two indirect effects constituted competitive mediation, with opposing directions that statistically offset each other. Competitive psychological climate simultaneously strengthened both pathways. These findings advance the understanding of AI's paradoxical effects on knowledge behavior and offer practical implications for organizations managing AI adoption alongside knowledge governance.
Honeybee venom (Apis mellifera), or apitoxin, is an emerging pharmaceutical starting material with significant potential in neurobiology and oncology. Despite its biochemical complexity, current industrial standardization predominantly relies on melittin as a lone univariate marker for quality assessment, a practice that neglects the interdependent nature of its molecular matrix. This study critically evaluates the "melittin-equivalence paradox"-a phenomenon where apitoxin batches with nearly identical melittin content exhibit profound multivariate divergence in their enzymatic and neurotoxic profiles. Utilizing a high-performance liquid chromatography (HPLC-DAD) framework validated according to ICH Q2(R1) guidelines, 25 bee venom batches from diverse ecological regions of Türkiye were interrogated. A chemometrics-based Multivariate Quality Assurance (MVQA) framework, integrating Principal Component Analysis (PCA), Z-score compositional profiling, and Distance-from-Centroid (DfC) analysis, was developed to resolve the paradox. Quantitative analysis revealed average concentrations of melittin (35.83% ± 3.36%), phospholipase A2 (PLA2, 14.16% ± 1.42%), and apamin (1.90% ± 0.18%). Case-based contrasts of melittin-matched samples (e.g., Case A: 32.1% and Case B: 31.7%) exposed significant uncoupled variations in PLA2 (12.31% vs. 11.00%) and moisture content (8.59% vs. 10.99%). PCA confirmed a critical orthogonality between the primary peptide fraction (PC1: 44.17%) and the enzymatic-physicochemical profile (PC2: 29.06%), demonstrating that melittin abundance is not a reliable proxy for the overall biochemical signature. The findings suggest that the "melittin-equivalence" often observed in traditional protocols is a univariate oversimplification that masks fundamental differences in stability and safety. The proposed MVQA framework provides a metrological roadmap for the standardization of bee venom, ensuring therapeutic consistency and safety through advanced chemometric protocols that go beyond single-parameter proxies.
Right-sided infective endocarditis (RSIE) commonly causes septic pulmonary embolism, whereas systemic manifestations typically suggest concomitant left-sided infective endocarditis or an intracardiac right-to-left shunt such as patent foramen ovale (PFO). A 24-year-old man with atopic dermatitis presented with fever and painful distal extremity skin lesions. Three sets of blood cultures grew Staphylococcus aureus. Transthoracic echocardiography (TTE) revealed a highly mobile, club-shaped vegetation (18.6 × 10 mm) adjacent to the tricuspid valve with severe tricuspid regurgitation due to leaflet perforation. Agitated-saline contrast TTE demonstrated right-to-left shunting with Grade III microbubble appearance in the left heart after five cardiac cycles following release of Valsalva manoeuvre, whereas no microbubbles were detected in the left heart at rest. Transoesophageal echocardiography confirmed no PFO and no left-sided vegetation. Chest computed tomography (CT) demonstrated multiple pneumonia and lung abscesses with cavities, consistent with septic pulmonary embolic disease, and discitis was confirmed on magnetic resonance imaging. Skin biopsy of the distal extremity lesions was consistent with septic micro-embolization. Empirical intravenous antibiotics were initiated and then tailored to susceptibility results. Antibiotic therapy continued for 6 weeks from the first documented negative blood culture. The vegetation regressed without surgery and pulmonary lesions improved. At 12-month follow-up, chest CT showed improvement of lung complications, and repeat agitated-saline contrast TTE suggested disappearance of right-to-left shunting. This case represents a plausible mechanism of paradoxical systemic manifestations in RSIE via a transient intrapulmonary shunt during severe septic pulmonary embolic disease.
The Tibetan Plateau is a major regulator of Asian hydroclimate, yet rapid changes in atmospheric demand are reshaping its water balance. Here, we examine whether the evaporation-paradox pattern has reversed by analysing meteorological records from 2000 to 2024 across the Nyainqêntanglha Mountains. Potential evapotranspiration (ET0) increased across the region, but the mechanisms were strongly elevation dependent. In low-elevation valleys, ET0 rebound was driven mainly by recovering wind speed and an expanding vapour pressure deficit, indicating increasing aerodynamic control. By contrast, high-altitude areas showed a cloud-brake effect, in which topographically enhanced cloudiness reduced radiation input and constrained ET0 growth despite pronounced warming. Explainable machine-learning analyses showed that the dominant predictors identified by XGBoost and Random Forest were broadly consistent with Penman-Monteith sensitivity. Long Short-Term Memory models further reproduced ET0 dynamics with strong predictive skill, supporting their use as virtual observation tools in data-sparse alpine environments. These findings indicate a transition from an energy-limited regime towards more dynamically controlled evaporative demand, with important implications for plateau water resources.
Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. While identifying drivers of tumor progression is critical, the molecular alterations specifically associated with T-stage advancement remain poorly understood. This study aimed to investigate genes linked to T-stage progression in PM using The Cancer Genome Atlas (TCGA) data, with a focus on the previously unreported roles of PRR11 and HEPACAM in this disease. RNA-sequencing data and clinical information for 87 PM patients were obtained from the TCGA database. After excluding patients with missing survival data, 43 patients were included in the survival analysis. Differential expression analysis was performed between advanced (T3-T4) and early (T1-T2) T-stage tumors using DESeq2. Survival analysis was conducted using Kaplan-Meier curves and multivariate Cox proportional hazards models. Associations between gene expression and T stage were evaluated, and the correlation between PRR11 and HEPACAM was assessed using Spearman correlation analysis. A total of 116 differentially expressed genes (DEGs) were identified between T3-T4 and T1-T2 tumors. While PRR11 was the most significantly upregulated gene in the overall DEGs analysis (log2FC =5.87), its expression showed no significant difference when directly comparing T3-T4 to T1-T2 groups (P=0.44). However, in multivariate analysis, high PRR11 expression emerged as an independent prognostic factor for worse overall survival (OS) [hazard ratio (HR) =2.74, P=0.005]. In contrast, HEPACAM, identified as the most significantly downregulated gene in the DEG analysis (log2FC =-5.10), exhibited paradoxically higher expression in advanced T-stage tumors compared to early-stage tumors (P=0.01). HEPACAM expression showed no significant association with OS (log-rank P=0.3). Notably, a significant negative correlation was observed between PRR11 and HEPACAM expression (Spearman's ρ =-0.375, P=0.01). This study reveals divergent roles for PRR11 and HEPACAM in PM. PRR11 is a robust independent prognostic biomarker, despite its lack of correlation with local tumor invasion as defined by T stage. HEPACAM demonstrates a complex, stage-dependent expression pattern, suggesting a potential context-dependent role in late-stage tumor biology. The inverse correlation between these genes may reflect opposing cellular programs in PM progression. These findings provide new insights into the molecular heterogeneity of PM and highlight the importance of integrating multiple analytical approaches when interpreting transcriptomic data.
The incorporation of immune checkpoint inhibitors (ICIs) into the treatment repertoire for hepatocellular carcinoma (HCC) and advanced biliary tract cancers has significantly transformed the field of oncology, offering remarkable survival advantages. However, the interaction of these powerful immunomodulators with liver transplantation (LT), the ultimate curative intervention for end-stage liver disease, presents a complex immunological paradox. While LT depends on the induction and maintenance of immune tolerance to suppress alloimmune responses and prevent allograft rejection, ICIs operate by disrupting these tolerance mechanisms to enhance host antitumor immunity. This comprehensive review synthesizes the latest evidence from 2024 and 2025, incorporating key findings from the VITALITY study, international washout cohorts, and meta-analyses of individual patient data. The historical "Liver Tolerance Effect," the mechanistic role of the PD-1/PD-L1 axis as a crucial protector of hepatic integrity, and the severe phenomenon of ICI-induced fatal hepatic necrosis are critically examined in this review. Furthermore, the emerging utility of precision predictive biomarkers, including immune-related adverse events (irAEs), the Eplet Risk Score, and intragraft PD-L1 expression as tissue-based predictors of post-transplant ICI-induced rejection, was rigorously analyzed to stratify rejection risk. By examining the pharmacodynamic conflict between systemic tumor eradication and localized graft preservation, this report provides a pragmatic, evidence-based framework for candidate selection, optimal washout timing, and post-transplant management, ultimately culminating in a critical appraisal of the ethical imperatives surrounding living donor liver transplantation.
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While the left ventricular (LV) hypertrophy and diffuse interstitial fibrosis characteristic of the pathophysiology of aortic stenosis (AS) are reversed by aortic valve replacement (AVR), the definitive treatment for AS, angiotensin modulators have demonstrated antifibrotic effects in animal models of AS. While goal-directed medical therapy (GDMT) treatment of hypertension is recommended for the early progressive stages of AS, there are no guideline-recommended antihypertensive therapies for stage D low-flow, low-gradient (LFLG) severe AS. All echocardiographic studies performed at South Shore University Hospital between January 2020 and December 2024 were retrospectively reviewed to identify a cohort of patients with LFLG severe AS. The progression of echocardiographic hemodynamic severity parameters was then examined according to prescribed antihypertensive medications in this cohort of 218 patients followed for a mean period of 19.1 months. In this cohort, the prevalence of LFLG severe AS with preserved left ventricular ejection fraction (LVEF) was 72.9%. Angiotensin-converting enzyme (ACE) inhibitors were not associated with any statistically significant change in hemodynamic severity markers, whereas angiotensin receptor blockers (ARBs) were associated with a statistically significant increase in peak jet velocity in a subset of the cohort (p = 0.042). In this cohort, angiotensin modulators were not associated with slower progression of AS severity parameters. Rather, the GDMT members - ​​​​sodium-glucose cotransporter 2 (SGLT2) inhibitors and beta-blockers - were associated with differential reductions in stenosis severity markers in patients with LFLG severe AS.
The cGAS-STING signaling pathway exhibits functions in breast cancer that include both antitumor immunity and pro-metastatic inflammation, transcending traditional linear switch models. To address this cognitive bottleneck, this paper proposes the conceptual framework of "cGAS-STING pathway-guided signal flow." It attributes pathway outcomes to multi-level fine-tuning, aiming to decipher initial immunogenic/pathogenic signals in the upstream phase based on intensity, duration, and origin. It elucidates how the STING protein, as a central hub, integrates and programs signals through a complex network of post-translational modifications at the midstream, thereby determining whether downstream effector branching favors the IFN-I-mediated antitumor axis or the NF-κB-driven pro-metastatic inflammatory axis. Based on this framework, this paper examines the key checkpoints at each level to explore in depth how to precisely regulate the cGAS-STING signaling pathway in order to maximize antitumor immune responses while mitigating potential risks of metastasis. This navigational framework clarifies signal branching mechanisms between the IFN-I antitumor axis and the NF-κB metastasis-promoting axis in breast cancer, identifies key nodes in signal branching, and evaluates the STING regulatory characteristics of various molecular subtypes. This provides both theoretical and practical foundations for signal reprogramming interventions, patient stratification, and the optimization of combination therapies.
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Lateral medullary syndrome (LMS), or Wallenberg syndrome, typically arises from ischemia of the dorsolateral medulla and is characterized by crossed sensory deficits, ipsilateral cranial nerve involvement, cerebellar ataxia, and Horner's syndrome. We report a 66-year-old hypertensive female who presented with classical clinical features suggestive of LMS, including ipsilateral facial sensory loss, contralateral body sensory impairment, palatal weakness, ipsilateral Horner's syndrome, and cerebellar signs. However, diffusion-weighted magnetic resonance imaging revealed a predominantly paramedian pontine tegmental infarction with associated right cerebellar involvement, without evidence of medullary ischemia. This clinico-radiological dissociation can be explained by the involvement of shared neuroanatomical pathways, such as the spinothalamic tract, spinal trigeminal nucleus, and descending sympathetic fibers, which extend into the pontine tegmentum, thereby mimicking LMS. This case highlights the limitations of clinical localization in posterior circulation stroke and emphasizes the importance of neuroimaging in accurately identifying lesion sites when brainstem syndromes present with overlapping features.
Vitiligo-like depigmentation (VLD) is a recognized cutaneous adverse event associated with anti-programmed cell death protein-1 (anti-PD-1) therapy in patients with melanoma and has been linked to favorable therapeutic response and improved survival outcomes. We present the case of a 72-year-old woman diagnosed with metastatic nodular melanoma treated with nivolumab monotherapy, who developed disseminated VLD after multiple treatment cycles. Despite achieving an initial complete radiologic response and developing extensive depigmentation, the patient subsequently experienced disease progression, presenting hepatic, pulmonary, and central nervous system metastases. This case contrasts with the commonly reported association between VLD and favorable prognosis, emphasizing that this phenomenon may not consistently predict sustained clinical benefit in patients receiving immunotherapy for advanced melanoma.
Autophagy plays a critical role in dynamic cell growth under different environmental conditions and maintains cellular homeostasis and cell viability in response to different cellular injuries, especially in tumor angiogenesis, where there is a controversial dual role. Angiogenesis plays a key role in facilitating tumor development. Therefore, investigating the mechanism of action of autophagy in the flexible shift of tumor angiogenesis is essential for antiangiogenic clinical therapy, and modulating the autophagy process is expected to constitute a new strategy to inhibit tumor angiogenesis and stop tumor growth and spread. This review highlights the close connection between autophagy and tumor angiogenesis. We also attempt to explain the seemingly contradictory promotion or inhibition of angiogenesis in tumor development reported in past studies. We focus on the potential clinical value of autophagy agonists and inhibitors in antiangiogenic therapy, which will provide new theoretical bases for antitumor therapy and may lead to innovative therapeutics.
Autosomal dominant osteopetrosis (ADO) is a rare bone disorder caused by impaired osteoclastic resorption. Despite high bone mass, ADO is paradoxically associated with increased fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides unique, low-radiation assessments of bone, but prior studies in ADO are limited to small case series. Using baseline cross-sectional data from an ongoing natural history study, we characterized HR-pQCT phenotypes in adults with ADO and explored associations with self-reported fracture history and bone turnover markers. HR-pQCT outcomes at the distal ends and shafts of the radius and tibia in 48 adults with ADO were compared to 144 matched controls (1, 3 ratio). In addition, z-scores for outcomes in ADO were calculated using established reference data. At trabecular-rich distal sites, ADO demonstrated markedly elevated total volumetric bone mineral density (vBMD), trabecular vBMD, trabecular bone volume fraction, trabecular thickness, and estimated failure load (all p<0.001), with values often approaching or exceeding twice those in controls. At cortical-rich shaft sites, total vBMD, bone area, bone area fraction, and cortical thickness were greater in ADO (all p<0.05). However, there was considerable interindividual variability, with some individuals having normal z-scores while others exhibited z-scores exceeding +20. The phenotype reflected increased bone mass rather than mineralization-cortical vBMD was normal and tissue mineral density was normal-to-lower in ADO. Outcomes at both distal and shaft sites were strongly correlated with lifetime fracture number (Spearman ρ=0.64-0.75, p<0.001), indicating ADO individuals with the "strongest" bones (via micro-finite element modeling) reported most fractures. The outcomes were correlated inversely with serum C-telopeptide and positively with serum tartrate resistant acid phosphatase 5b, consistent with ADO being rich with dysfunctional osteoclasts. Overall, the data reveal the profound, yet variable, phenotype in ADO and indicate that HR-pQCT measures correlate with disease severity and represent potential surrogate endpoints for future therapeutic trials. Autosomal dominant osteopetrosis (ADO) is a rare genetic bone disorder wherein bone-removing cells do not work properly, leading to bones that are dense yet fragile. Using specialized bone scans, we compared 48 adults with ADO and to healthy individuals. People with ADO had greatly increased bone mass and abnormal internal bone structure, though results varied widely. Those with the most extreme abnormalities reported the most fractures, despite scans estimating their bones to be “strongest”. This paradox shows that bone quality—not just quantity—is impaired in ADO. This study also identifies scan measures that may help track disease progression in future trials.
Pneumonia remains a leading cause of morbidity and mortality worldwide. The COVID-19 pandemic has significantly altered the epidemiological landscape of respiratory infections. Understanding current etiological patterns and risk factors is crucial for optimal patient management. To characterize the etiological spectrum of pneumonia and identify clinical and laboratory factors associated with both in-hospital and post-discharge mortality in a large cohort of patients treated during the COVID-19 era. We conducted a retrospective analysis of 1,848 adult patients hospitalized with pneumonia at a tertiary care hospital in Linz, Austria, between January 2020 and January 2024. Data included demographics, comorbidities, laboratory findings, microbiological results, and mortality outcomes. Statistical analyses included univariate correlations and Cox regression models for survival analysis. Etiological agents were identified in only 26.4% of cases, with SARS-CoV-2 being the most frequently detected pathogen (8.7%). In-hospital mortality was 15.1%. Significant risk factors for in-hospital mortality included chronic kidney disease (φ = 0.057, p = 0.015), dysphagia (φ = 0.061, p = 0.009), malignancy (φ = 0.086, p < 0.001), and detection of specific pathogens including Candida albicans, Staphylococcus aureus, and Enterobacter cloacae. Higher HDL levels (r = -0.120, p < 0.001) and longer hospital stays were associated with improved survival. Post-discharge mortality risk factors included advanced age, elevated CRP levels, and multiple comorbidities, while obesity demonstrated a paradoxical protective effect (HR = 0.628, p = 0.015). This study reveals a high rate of unidentified pathogens and identifies specific clinical and microbiological factors associated with pneumonia outcomes during the COVID-19 era. The obesity paradox and protective effect of HDL cholesterol warrant further investigation.
Futility is difficult to define in the context of Cardiopulmonary Resuscitation , as it refers to the low likelihood of success. Healthcare providers face challenges when performing pediatric/neonatal Resuscitation. This study aimed to explore the lived experiences of resuscitation team members regarding futile Cardiopulmonary Resuscitation in children/newborns. A qualitative descriptive phenomenological approach was used with purposive sampling, resulting in 11 members of the Cardiopulmonary Resuscitation team for children/newborns (7 nurses/4 physicians). Data were collected through in-depth, semi-structured interviews conducted online/face-to-face and analyzed using Colaizzi's descriptive phenomenological method. Findings revealed two main themes: "useful or traumatic futile resuscitation; the paradoxical feelings," and "the tension of attempting resuscitation despite knowing it is futile."The first theme included "justifying the usefulness of futile resuscitation" and "examining the adverse outcomes of futile resuscitation," while the second included "coercion to futile resuscitation for others' interests," "symbolic resuscitation for social-legal reasons," and "coercion to futile resuscitation for the resuscitator's benefit." Participants perceived a paradox between futility and usefulness based on their values, beliefs, experiences, and interpretation of consequences. Facing this dichotomy under pressure to perform futile resuscitation created distressing experiences. Given the absence of clinical guidelines for do-not-resuscitate, developing such guidelines is essential to prevent confusion and moral distress among health professionals.