Publications

Pseudomonas aeruginosa is a clinically significant, opportunistic pathogen adept at thriving in both host-associated and environmental settings. We sought to define the extent to which P. aeruginosa isolates specialize across niches using a comprehensive study of whole-genome sequencing with paired phenotypic characterization of 125 P. aeruginosa isolates from diverse clinical and environmental sites. We evaluated virulence-associated traits, including motility, cytotoxicity, biofilm formation, pyocyanin production, and antimicrobial resistance to eight antibiotics. Our results show that genomic diversity does not correlate with isolation source or most virulence phenotypes. Instead, we find that, in agreement with prior studies, the two major P. aeruginosa clades (groups A and B) clearly segregate by cytotoxicity, with group B strains showing significantly higher cytotoxicity than group A. Sequence analysis revealed previously uncharacterized alleles of genes encoding type III secretion effector proteins. We observed high variability among strains and isolation sources in the four assayed virulence phenotypes. Antimicrobial resistance was exclusively observed in clinical isolates, whereas it was absent in environmental isolates, reflecting antibiotic exposure-driven selection. Bacterial genome-wide association studies (GWAS) revealed an association between cytotoxicity and exoU presence, and we identified a novel exoU allelic variant with decreased cytotoxicity, demonstrating that functional diversity of well-characterized virulence factors may influence pathogenic outcomes. Overall, our analysis supports the hypothesis that the ability of P. aeruginosa to thrive across diverse niches is driven not by niche-specific accessory genes but by its core genome. Thus, P. aeruginosa isolates are capable of broad niche colonization without initial genetic adaptations.IMPORTANCEPseudomonas aeruginosa is a clinically significant opportunistic pathogen adept at thriving in both host-associated and environmental niches. A major gap in our understanding of this difficult-to-treat pathogen is whether niche specialization occurs in the context of human disease. Addressing this question is critical for guiding effective infection control strategies. Previous large-scale studies have focused solely on genotypic or phenotypic analyses; when paired, they have been limited to a single phenotypic assay or to a small number of isolates from one source, or relied on PCR-based methods targeting a restricted set of genes. To comprehensively uncover niche specialization and pathogenic versatility, we performed whole-genome sequencing and phenotypic characterization of five virulence-associated traits, including antimicrobial susceptibility of 125 clinical and environmental P. aeruginosa isolates. Our systems-level findings challenge reductionist models of bacterial niche specialization, instead supporting an integrated view where conserved genomic systems enable opportunistic pathogenesis across diverse environments.

Women's health remains inadequately served due to the historical predominance of males as the biological reference in medical research, leading to persistent sex-based gaps in the understanding, diagnosis, and management of disease. As healthcare moves toward decentralization, e.g., through the collection of person-generated health data, point-of-care diagnostics, and wearable devices, there is a critical need for tools tailored to women's unique conditions and presentations. Ultrasound technologies, recognized for their versatility and safety, have evolved from imaging to multifunctional platforms, with growing roles in diagnosis and therapy. Diagnostic ultrasound non-invasively assesses anatomical features and functional information, and therapeutic ultrasound can perform targeted interventions, including neuromodulation, immunomodulation, thermal ablation, and drug delivery. By exploring the fundamental physical principles of ultrasound, including acoustic streaming, cavitation, and thermal interactions, and linking these mechanisms to cellular and tissue responses, this review highlights the capability of ultrasound to address female-specific health disparities, especially in conditions that are undertreated or differentially expressed in women. Advancements in ultrasound technologies could significantly enhance clinical outcomes and improve the quality of life for women affected by conditions currently underserved by traditional medical interventions.

Fear is an evolutionarily adaptive mechanism that enables organisms to detect and respond to potential threats. Over the past century, theories of fear have evolved from Pavlovian and behavioral frameworks to neuroscientific models that emphasize specific neural circuits, neurotransmission, and plasticity. This pictorial review synthesizes key concepts underlying the neuroscience of fear, starting with a historical narrative of fear as conceptualized by conditioning and behaviorism theories, to the roles of different neurobiology structures, networks, to concepts of memory consolidation, reconsolidation, and plasticity. We highlight how pathological fear is implicated in disease, integrating evidence from conditioning theories, neuroscience, and additional considerations (ie. Culture and psychosocial context). Finally, we outline therapeutic approaches that leverage neuroscience to target maladaptive fear circuits. Understanding these mechanisms provides a foundation for advancing personalized treatments for fear-related psychopathology.

Deficient extinction learning and memory are hypothesized mechanisms for pathological anxiety that are associated with sleep disturbance. fMRI neural activations to threat conditioning, extinction learning, and extinction recall were measured. Activations were compared, in persons with Generalized Anxiety Disorder (GAD), between those with moderate to severe Insomnia Disorder (ID) and those with absent or sub-threshold ID. Relationships of activations with measures of sleep quality and physiology were examined. Between-group comparisons and whole-sample correlation with sleep parameters were examined in relation to large-scale brain networks using a liberal cluster-determining threshold. Localized activations were then identified using family-wise error correction. Activations to the reinforced stimulus (CS+) that increased from the beginning to end ("across") threat conditioning were more extensive within the GAD+ID group. Increased activations to the CS+ across extinction learning were greater within the GAD-ID than the GAD+ID group, and delayed 24 h in the latter. Greater sleep efficiency was associated with decreased activations across threat conditioning, but with increased activations across extinction learning. Better sleep quality promoted greater engagement of neural substrates of extinction learning. The GAD+ID group failed to engage brain areas supporting extinction learning immediately following threat conditioning, but did so when stimuli were again presented following a delay.

Direct measurement of mitochondrial oxygen tension in vivo provides direct information on tissue metabolism and could facilitate new approaches in disease detection, function monitoring, and treatment efficacy assessment with cellular level data, with far superior sensitivity to oxygen changes than blood saturation measures. Here, a platform system was engineered to quantify fast sampling of oxygen partial pressure (pO2) inside tissue by utilizing the inherent rolling shutter readout of a smartphone CMOS camera detector for measuring the oxygen-sensitive time-resolved delayed fluorescence (DF) signal from Protoporphyrin IX (PpIX) which naturally occur in mitochondria for most tissues. The CMOS rolling shutter readout produces a microsecond-level time difference in the pixels row-by-row detection of light, here utilized as a time-gated shutter to sample the time distributed DF intensity. This novel technique eliminated the necessity of high-speed intensified camera with excitation isolation facility as well as advanced precise time synchronization system as required in the conventional time-resolved fluorescence lifetime measurement platforms for quantifying time-dependent very low intensity DF distribution of PpIX conjugated with prompt fluorescence. Both steady state and dynamic performance of the instrument were validated in tissue phantoms at different PpIX concentrations (0.5-10 μM) for wide range of pO2 detection (0-160 mmHg) with tunable fast response time (1-3.5 s) which is substantially faster than electrode-based systems that measure over 10's of seconds. Finally, it was tested in vivo to assess the impact of dynamic inhaled oxygen concentration variation on skin tissue pO2 under the conditions of normoxia, hyperoxia and hypoxia.

BACKGROUND: Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising biomarkers for Multiple Sclerosis (MS) disease activity. There is less known about their association with the symptomatic phenotypes such as depression and mental health outcomes.

OBJECTIVES: To investigate the association between sNfL and sGFAP and Patient-Reported Outcome (PRO) measures for depression and overall mental health in individuals with MS (iwMS).

METHODS: Participants completed the Center for Epidemiological Studies Depression Scale (CESD) and MS Quality of Life-54 (MSQOL-54)- at the time of the blood draw. Linear regression was used to estimate the association between the PRO measures as the outcome and the log-transformed biomarkers as the predictor. The association between baseline biomarkers and longitudinal change in PROs was estimated using linear mixed-effect models.

RESULTS: Cross-sectional analysis showed a significant correlation between sNFL and CES-D (p = 0.035) and MSQOL-54 Mental Health Composite (MHC) (p = 0.003) scores. This association remained statistically significant after adjusting for sex, age, EDSS and MS treatment. Neither cross-sectional nor longitudinal analysis of sGFAP levels showed significant correlation with PROs scores.

CONCLUSION: Serum NfL is associated with depression and overall mental health scores in iwMS. We did not find a significant relationship between sGFAP and PRO measures.

Cardiac glycosides (CGs) such as ouabain exert positive inotropic effects by inhibiting the Na+-K+-ATPase. CGs' wide spread use is limited by CGs' narrow therapeutic window. Mis- or overdosing with CGs may cause cardiac arrhythmias, resulting from electrolyte disturbances. To study the ethically challenging topic of CG overdosing, we here optimized the in ovo platform to test whether treatment with the selective ouabain antagonist rostafuroxin prevents CG-mediated electrophysiological derangements and arrhythmia by restoring electrolyte homeostasis. We used incubated chicken eggs (iCEs), a 3 R-compliant model, for which we established electrocardiograms (ECGs). ECGs were recorded under 1) baseline conditions, 2) after treatment with ouabain, and 3) after cotreatment with rostafuroxin. Underlying mechanisms of ouabain and rostafuroxin effects were studied using blood gas analysis and fluorescence microscopy. Isolated murine and human cardiomyocytes served as an independent model to confirm in ovo results. Ouabain treatment resulted in increased heart rate variability (HRV), transient sinus arrest, and atrio-ventricular dyssynchrony, accompanied by plasma hyperkalemia and cardiomyocyte Na+ overload. Cotreatment of ouabain and rostafuroxin led to reduced HRV and ameliorated the frequency and duration of transient sinus arrest, whereas plasma K+ levels remained unchanged. In isolated cardiomyocytes, ouabain treatment induced intracellular Na+ overload, which was abolished by additional rostafuroxin treatment. Our work demonstrates the in ovo platform and corresponding readouts as a suitable tool to study cardiac electrophysiology in a 3 R-compliant manner. We found that rostafuroxin treatment ameliorated ouabain-induced electrophysiological disturbances, suggesting rostafuroxin as a potential therapeutic intervention for ouabain mis- or overdosing.NEW & NOTEWORTHY This study evaluates rostafuroxin, a selective ouabain inhibitor, for its potential to antagonize electrophysiological derangements in ouabain overdosing. Methodologically, the study uses the iCE model, previously introduced as a suitable 3 R-compliant cardiovascular research platform. We developed and validated a comprehensive electrophysiological workflow in iCEs to perform our investigations. Ouabain increased heart rate variability, induced arrhythmia and electrolyte imbalances in iCEs, whereas rostafuroxin largely protected them from these effects.

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NSAID-ERD) is a heterogeneous condition characterized by chronic eosinophilic airway inflammation in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma whose symptoms are aggravated after ingestion of aspirin and other NSAIDs. As a unique treatment, aspirin treatment after desensitization (ATAD) has been in use for several years after showing the inhibitory effect on CRS symptoms and nasal polyp growth as well as severe asthma. However, in recent years, biologics have also shown to cause a decrease in polyp size as well as associated outcomes such as quality of life. In this manuscript, considerations on choosing the best treatment of NSAID-ERD are laid out based on current literature.

BACKGROUND: The antithrombotic strategies for symptomatic intracranial atherosclerotic stenosis (sICAS) remains challenging. Dual pathway inhibition (DPI) has demonstrated clinical benefit in coronary and peripheral artery disease.

AIMS: This study aimed to evaluate the efficacy of DPI with low-dose rivaroxaban plus antiplatelet therapy (APT) compared with APT alone on recurrent stroke with sICAS.

METHODS: This prospective cohort study included patients with sICAS identified from the Ischemic Cerebrovascular Disease Database of the First Affiliated Hospital of Zhengzhou University between January 2019 to August 2023. Low-dose rivaroxaban was prescribed off-label to patients in the DPI group. The outcomes were ischemic stroke, transient ischemic attack (TIA), acute coronary syndrome (ACS), all-cause death and cardio-cerebrovascular death within 1 year of discharge. Cox regression with inverse probability of treatment weighting (IPTW) was applied to compare outcomes between the DPI and APT groups. The win-ratio method was used to assess the major adverse cardiovascular events (MACE), prioritized in the order of all-cause death, recurrent ischemic stroke or TIA, and ACS.

RESULTS: Among the 1217 patients with sICAS, 131 (10.8%) received DPI therapy. The recurrence rate of ischemic stroke was lower in the DPI group compared to the APT group (8/131 [6.1%] vs 136/1086 [12.5%]). DPI significantly reduced the risk of ischemic stroke recurrence (HR = 0.46, 95% CI: 0.23-0.94, p = 0.034) and the incidence of MACE (HR = 0.53, 95% CI: 0.29-0.97, p = 0.041) during the 1-year follow-up, consistent with the IPTW-based cohort (HR = 0.35, 95% CI: 0.16-0.76, p = 0.008; HR = 0.43, 95% CI: 0.22-0.83, p = 0.012). The win-ratio analysis of MACE favored DPI therapy (win ratio = 2.34, 95% CI: 1.41-3.90, p = 0.001). Symptomatic intracranial hemorrhage, fatal bleeding, and hospitalization for gastrointestinal bleeding were infrequent in this cohort.

CONCLUSIONS: DPI therapy may be associated with a lower risk of recurrent stroke compared with antiplatelet therapy alone in patients with sICAS. These findings warrant further investigation through large-scale randomized controlled trials.

INTRODUCTION: Catheter-based interventions (CBI) have yielded promising data in selected patients with acute pulmonary embolism (PE). Despite growing clinical use, high-quality comparative evidence on the efficacy and safety of CBI, especially in relation to standard anticoagulation or systemic thrombolysis, is limited. As new randomized controlled trials (RCTs) rapidly accumulate, this living evidence synthesis will aim to systematically and continuously evaluate the comparative efficacy and safety of reperfusion strategies vs standard of care in patients with high- and intermediate-risk acute PE.

METHODS: This living systematic review and meta-analysis will include RCTs comparing reperfusion strategies to standard of care in adult patients with high- or intermediate-risk PE. The primary analysis will pertain to trials that are powered and designed to assess hard clinical outcomes, such as death and hemodynamic deterioration. A secondary analysis will include additional studies reporting clinical outcomes, including those primarily evaluating hemodynamic or surrogate outcomes. Analyses will be stratified by PE severity (high- and intermediate-risk) and also conducted using a frequentist network meta-analysis framework. The review is ongoing, with new eligible trials added prospectively.

RESULTS: As of the initial search on 28 May 2025, 23 RCTs are included. Thirteen additional ongoing trials were identified for future inclusion, including trials with clinical outcomes such as PEITHO-3, HI-PEITHO, PEERLESS II, PE-TRACT, and PRAGUE-26 for intermediate-risk PE, and CATCH-PE II, PERSEVERE, and TORPEDONL for high-risk PE.

CONCLUSION: This living meta-analysis will offer continuously updated, comparative evidence on reperfusion strategies for acute PE, with a focus on informing the role of catheter-based interventions in clinical decision-making.

REGISTRATION: PROSPERO: CRD420251207053. Available from https://www.crd.york.ac.uk/PROSPERO/view/CRD420251207053.