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Could the load of carbapenemase genes in hospital wastewater be a proxy for emerging resistance to carbapenems in humans?
No full textAbstract Background Antimicrobial resistance (AMR) poses a growing threat to global public health and is a key concern for infection control teams in hospitals. However, AMR surveillance is time-consuming and limited in most countries, resulting in incomplete findings. In high-income countries, infection control teams ensure the contact tracing of every patient carrying an emerging extensively drug-resistant bacterium which is very time-consuming. Wastewater surveillance (WWS) has been proposed as an alternative approach for the surveillance of infectious diseases. This study aims to test the feasibility of AMR WWS under real-world conditions in hospital. It investigates the dynamics of endemic (bla CTX-M) and emerging AMR genes (bla OXA-48, bla NDM, bla KPC and vanA) in wastewater from two hospital buildings where patients with contrasting risk for carrying resistant bacteria were cared for and compares results with clinical data. Methods The sampling programmes were adapted according to the sampling sites and patient flow for each hospital building. Genes were quantified in the effluent using qPCR and dPCR. Cultivable carbapenemase-producing Gram-negative bacteria were characterised using MALDI-TOF MS and PCR. Results The feasibility of AMR monitoring in wastewater in real hospital conditions was demonstrated by dPCR and qPCR, which produced correlated results. The presence of peaks and the low load of the vanA and bla NDM genes in wastewater (compared to bla CTX-M) were consistent with their known emerging status, as indicated by national and local clinical data. However, the high concentration of bla OXA-48 and bla KPC in wastewater was unexpected because it did not reflect the known clinical involvement of these emerging resistances, particularly in the case of bla KPC. Bacterial culture also revealed discrepancies between the species isolated in wastewater and those isolated in patients in the hospital, with a majority of Citrobacter spp. carrying bla KPC and bla OXA-48 in wastewater, whereas Escherichia coli and bla OXA-48 dominated in patients. Quantifying carbapenemase genes in wastewater was able to differentiate between buildings housing patients contrasting risks of emerging AMR. Conclusion This study shows the WWS feasibility in real hospital conditions and preliminary findings regarding patient populations but identified obstacles that need to be overcome prior to use WWS for routine surveillance in an infection control hospital context
T-cell-targeted fusogenic nanovesicles generate CAR-T cells in vivo for rheumatoid arthritis therapy
No full textAbstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease in which pathogenic B cells drive persistent inflammation and joint damage. Although CD19-targeted CAR-T cell therapy enables effective B-cell depletion, conventional ex vivo manufacturing and viral vector-based genetic modification limit its scalability and clinical application. Strategies that allow efficient CAR-T cell generation directly in vivo may therefore provide a more practical approach to sustained immune modulation. Methods We developed FuNVCAR, a T cell-targeted fusogenic nanovesicle system that delivers preformed αCD19 CAR proteins to T cells via membrane fusion. FuNVCAR was characterized for size, composition, and fusion specificity. CAR-T cell generation, persistence, and cytotoxic function were evaluated in vitro. In vivo CAR-T induction, B-cell depletion, therapeutic efficacy, and tissue-level outcomes were assessed in a collagen-induced arthritis (CIA) mouse model. Results FuNVCAR selectively fused with CD3⁺ T cells and enabled dose-dependent surface display of functional αCD19 CAR proteins without genetic modification. FuNVCAR-generated CAR-T cells exhibited antigen-specific cytotoxicity against CD19⁺ B cells in vitro. In vivo administration induced measurable CAR-T cell generation in blood and spleen, resulting in effective B-cell depletion, reduced autoantibody levels, attenuation of joint inflammation, and preservation of cartilage and bone architecture in CIA mice. FuNVCAR showed favorable tolerability with no overt organ toxicity. Conclusions These findings demonstrate that FuNVCAR enables functional in vivo CAR-T cell generation and sustained disease modification in experimental arthritis. FuNVCAR represents a mechanistically distinct and scalable platform for CAR-T-based immunotherapy in RA and other B cell-driven autoimmune diseases
IgG4 Neutralization and Sustained Total IgG Fc-Effector Functions Following Repeated SARS-CoV-2 Vaccination with mRNA-1273
No full textAbstract Introduction Detailed characterization of the antibody profile induced by SARS-CoV-2 mRNA vaccines has shown that repeat dosing boosts all immunoglobulin G (IgG) subclasses, with a notable emergence of antigen-specific IgG4 antibodies. While the IgG4 subclass is traditionally associated with limited Fc-effector functions, its role in SARS-CoV-2 mRNA vaccine-induced immunity remains unclear. Methods This study tracked IgG subclass dynamics, IgG Fc-mediated functions, and neutralization following immunization with two or three doses of Moderna SARS-CoV-2 mRNA vaccine (mRNA-1273) in healthy adults. Results We observed robust spike-specific IgG1 and IgG3 responses after the primary series (two doses) and booster dose, with a significant increase in IgG4 responses after repeated dosing. Despite this rise in spike-specific IgG4 antibodies, strong Fc-effector functions were maintained at the overall IgG level, including antibody-dependent cellular phagocytosis, antibody-dependent neutrophil phagocytosis, and antibody-dependent complement deposition, with no antagonism from IgG4 antibodies. Additionally, IgG4 antibodies exhibited enhanced affinity and potent neutralization, complementing IgG1-driven responses. Conclusions These findings suggest that elevated IgG4 responses did not antagonize overall Fc-mediated effector mechanisms, indicating that mRNA-1273 induces a multi-subclass antibody response that preserves antiviral functionality. Trial Registration NCT04470427
Safety and Efficacy of Fecal Microbiota, Live-jslm for Prevention of Recurrent Clostridioides difficile Infection Among Hospitalized Participants in PUNCH CD3-OLS
No full textAbstract Introduction Fecal microbiota, live-jslm (RBL) is the first single-dose, microbiota-based product approved by the US Food and Drug Administration and Health Canada to prevent recurrent Clostridioides difficile infection (rCDI) following standard-of-care antibiotics. The phase 3 PUNCH CD3-OLS study enrolled participants with numerous comorbidities and permitted inclusion of participants hospitalized due to rCDI. The safety and efficacy of RBL were evaluated in this subgroup analysis of hospitalized participants from PUNCH CD3-OLS. Methods The hospitalization subgroup included participants hospitalized for rCDI within 90 days prior to RBL administration. Participants received a single dose of RBL 24–72 h after completion of standard-of-care antibiotic treatment for rCDI. These exploratory analyses evaluated the number of participants with RBL- or administration-related treatment-emergent adverse events (TEAEs), treatment success at 8 weeks, sustained clinical response at 6 months, and incidence of rehospitalization for rCDI during study participation. Results The hospitalization subgroup included 74 of 697 (10.6%) participants. Within 6 months following RBL administration, 47 (63.5%) and 350 (56.7%) participants in the hospitalization and nonhospitalization subgroups experienced TEAEs, respectively; most TEAEs were of mild to moderate severity. Serious TEAEs in the hospitalization subgroup were frequently related to preexisting conditions; none were related to RBL or its administration. Most participants (87.8% [65/74]) in the hospitalization subgroup were not rehospitalized within 6 months. Treatment success at 8 weeks was 62.5% (45/72) and 75.1% (449/598) among participants in the hospitalization and nonhospitalization subgroups, respectively. Of those achieving treatment success, 86.7% (39/45) and 91.3% (410/449) had sustained clinical response through 6 months in the hospitalization and nonhospitalization subgroups, respectively. Conclusion RBL was safe and effective in a subgroup of hospitalized participants in the PUNCH CD3-OLS study. Efficacy in this subgroup was slightly lower than in nonhospitalized participants, but rCDI-related rehospitalization remained rare. Trial Registration NCT03931941
Astrocyte CB1 receptors drive blood-brain barrier disruption in central nervous system inflammatory disease
No full textAbstract Reactive astrocytes shape central nervous system (CNS) inflammation and participate in myelin damage and repair mechanisms in multiple sclerosis (MS). Through the activation of cannabinoid CB1 receptors (CB1R) expressed by neurons and oligodendrocyte lineage cells, endocannabinoid signaling restricts neurodegeneration and promotes remyelination in preclinical MS models. However, despite accumulating evidence that supports cell-specific roles for CB1R in brain physiology and pathology, the implications of astrocyte CB1R signaling in MS initiation and progression remain uncertain. Using complementary in vivo disease models, here we investigated the effects of targeted genetic deletion of astrocyte CB1R on the expression of MS-like pathology in mice. Interestingly, astrocyte-specific deletion of CB1R reduced demyelinating neuropathology, attenuated astrocyte reactivity and improved clinical deficits during the time-course of experimental autoimmune encephalomyelitis (EAE). Mice with astrocyte CB1R inactivation displayed unaltered oligodendrocyte populations both in EAE plaques and in lysolecithin-induced remyelinating spinal cord lesions, likely excluding that CB1R expressed by astroglial cells modulate myelin repair processes. Conversely, inactivation of CB1R in astrocytes restricted humoral and leukocyte parenchymal infiltration and reduced the expression of vascular effectors in EAE lesions. Finally, loss of blood-brain barrier (BBB) function induced by cortical microinjection of VEGF-A was less severe in astrocyte CB1R null mice. These results show that astrocyte CB1R signaling constitutes a significant pro-inflammatory mechanism in experimental MS and bring to light a deleterious role for endocannabinoid-mediated modulation of astroglial cells with potential implications in the etiopathology and therapy of neuroinflammatory disorders
Mouse model for sensitivity of fluid measurement with textile electrodes
No full textAbstract Heart failure is a leading cause of morbidity and mortality, and fluid congestion complicates its management. Conventional home-monitoring methods, such as daily weight measurements, are insufficiently sensitive, while invasive techniques are impractical for routine use. This paper introduces a novel, non-invasive approach using textile-based dry electrodes for bio-impedance spectroscopy to detect subtle changes in thoracic fluid volume in a mouse model. Twenty-three mice underwent controlled fluid infusion into the thoracic cavity following a six-stage protocol. Bio-impedance data were collected over 256 frequencies ( 3 - 1000 kHz) and analyzed to extract R 0 and R ∞ , from which total ( V T ), extra-cellular ( V E ), and intra-cellular ( V I ) fluid volumes were calculated and normalized to baseline. Statistical analyses included two-way ANOVA and multiple linear regression to correlate impedance measurements with animal length and weight. No statistically significant differences in normalized fluid volumes ( V T , V E , V I ) were observed across infusion stages ( p > 0.05 ), though there was an anecdotal increase in V T ( Δ V T = 1.16 ± 1.79 mL) and V I ( Δ V I = 1.80 ± 2.91 mL) after fluid infusion. Multiple linear regression revealed moderate correlations between impedance measurements and weight ( r 2 = 0.33 , p = 0.035 , RMSE = 19.34 g) as well as length ( r 2 = 0.34 , p = 0.0066 , RMSE = 1.00 cm). Additionally, a strong correlation was found between length and weight ( r 2 = 0.81 , p = 5.65 × 10 - 8 ). The results indicate that textile-based dry electrodes can non-invasively measure thoracic fluid volume in mice, although the sensor’s sensitivity to small changes is limited. Further refinement is needed to enhance sensitivity and determine sensitivity threshold. These findings support the continued development of textile-based bio-impedance sensors as a practical tool for non-invasive heart failure monitoring
Sex hormone-responsive human vaginal epithelial organoids: a novel in vitro platform for studying Chlamydia trachomatis infection
No full textAbstract The vaginal epithelium, a hormone-sensitive barrier critical for reproductive health, lacks robust in vitro models due to primary tissue scarcity and existing systems’ limitations. Here, we established the first long-term, genetically stable human vaginal epithelial organoids (VEOs) using a tailored Matrigel-based culture medium that preserves the native stratified squamous architecture. Through transcriptomic and functional profiling, we identified progesterone as a key suppressor of immune defense and keratinization. Modeling Chlamydia trachomatis (CT) infection in VEOs recapitulated infection-induced reactive oxygen species (ROS) overproduction, senescence, and inflammation. Progesterone pretreatment significantly reduced ROS and cellular damage, suggesting hormonal modulation of cellular homeostasis. By integrating air-liquid interface (ALI) culture technique and exploring different proportions of Matrigel and collagen composition, we resolved the polarity limitations of three-dimensional (3D) organoids, enabling physiological modeling of infection-induced barrier dysfunction. This study establishes VEOs as a transformative model for dissecting hormone-microbe crosstalk in reproductive health and for accelerating therapeutic development against vaginal infections. Graphical Abstrac
Bacterial outer membrane vesicles: a smart platform for biomedical applications
No full textAbstract Outer membrane vesicles (OMVs) are non-replicating, nanoscale particles naturally released by Gram-negative bacteria, which play important roles in bacterial communication and host interactions. Due to their biocompatibility, efficient production through fermentation, and inherent lymph node targeting capability, OMVs have emerged as a promising platform for biomedical applications, including vaccine development, drug delivery, immune modulation, cancer therapy, and antimicrobial strategies. This review discusses the biogenesis and biological functions of OMVs, methods for their isolation, and recent advances in their engineering as drug delivery systems, with a focus on vaccines and immunoadjuvants. We also address key challenges in scalable production and purification, propose potential solutions, and highlight current limitations along with future research directions. Graphical abstract Bacterial outer membrane vesicles as a smart & multifunctional platform for biomedical applications
Drivers of citation impact in leading pharmaceutical sciences journals: a hybrid manual and API-driven bibliometric analysis
No full textAbstract Background Citations may be used as a metric of scholarly impact, yet traditional bibliometric approaches often rely on manual data extraction from citation databases that presents scalability constraints. Hybrid manual and Application Programming Interfaces API-driven approaches may be used to systematically identify predictors of citations in scientific journals. Objective To identify whether journal, thematic, methodological, geographic, open access, or promotion factors drive citations in three leading pharmaceutics journals and to evaluate a hybrid manual/API-driven approach for bibliometric data extraction and analysis. Methods A cross-sectional analysis of original research articles published between 2016 and 2018 in the AAPS Journal, the European Journal of Pharmaceutical Sciences, and the Journal of Pharmaceutical Sciences was conducted. Article metadata were extracted manually and using API pipeline (NCBI E-utilities, Google Scholar, Altmetric APIs). The dependent variable was citation count. Predictor variables included publication year, journal, study topic, design, geographic region, open-access status, route of administration, formulation type, therapeutic area, social-media mentions, number of disciplines, institutions, and references. The dependent variable was dichotomized using median number of citations, and multivariable logistic regression (α = 0.05) was used to identify independent predictors of citations above median. Results Of the 3,510 records identified, 3,252 original research articles met inclusion criteria. The median citation count was 23 (range 0–976). In the multivariable model, publications from 2017 (OR 0.784; 95% CI: 0.664–0.926) and 2018 (OR 0.581; 95% CI: 0.488–0.691) had lower odds of being cited above the median compared to 2016 papers. Among study designs, review articles had over threefold higher odds of being cited above the median compared to basic science studies (OR 3.385; 95% CI: 2.515–4.606). Modeling and simulation studies had lower odds of citations above median (OR 0.754; 95% CI: 0.612–0.927) compared to basic science studies. Animal-based research was less likely to be cited above the median compared to in-vitro studies (OR 0.611; 95% CI: 0.480–0.775). Papers with corresponding authors from Africa (OR 2.165; 95% CI: 1.341–3.590) and the Middle East (OR 1.936; 95% CI: 1.226–3.121) were more likely to be cited above the median compared to those from Europe. Papers with no specified route of administration (OR 0.803; 95% CI: 0.666–0.968) and those on parenteral drugs (OR 0.689; 95% CI: 0.549–0.863) were less likely to be cited above the median compared to articles on orally administered drugs. Open-access papers (OR 1.240; 95% CI: 1.064–1.454) and those with over two X mentions (OR 1.572; 95% CI: 1.135–2.191) were more likely to be cited above the median. Papers describing colloidal systems (microspheres/hydrogels) were more likely to be cited above the median (OR 1.598; 95% CI: 1.187–2.158) compared to articles on solid formulations. As for the therapeutic focus, infectious-disease studies were less likely to be cited above the median (OR 0.622; 95% CI: 0.500–0.774) compared to no specific disease articles. Each additional discipline increased the odds of the article being cited above the median by 20% (OR 1.205; 95% CI: 1.088–1.337), and each extra reference by 2% (OR 1.020; 95% CI: 1.017–1.024). Conversely, each additional collaborating institution reduced the odds of the paper being cited above the median by 10% (OR 0.896; 95% CI: 0.804–0.997). Conclusions Citation counts in pharmaceutics articles are influenced by various factors, including article type, methodology, geographic origin, open access status, and promotion via social media. The presented hybrid citation analyses may streamline future bibliometric research across pharmaceutics and other scientific fields. Graphical Abstrac
Elevated miR-409-5p may promote the progression of osteoarthritis by targeting DLST as a potential biomarker function of miR-409-5p in osteoarthritis
No full textAbstract Background Osteoarthritis (OA) significantly impairs the quality of life of middle-aged and elderly individuals. MicroRNAs (miRNAs) are known to play key regulatory roles in OA progression. Aims To investigate the potential role mechanisms of miR-409-5p in OA. Methods This study enrolled 93 OA patients and 75 non-OA controls. The expression levels of miR-409-5p, DLST, and OA-related markers were measured using RT-qPCR or Western Blot. The targeting relationship between miR-409-5p and DLST was verified by dual luciferase reporter assays. Cell viability was assessed with the CCK-8 assay, and inflammatory cytokine concentrations were measured via ELISA. Results Serum miR-409-5p expression was higher in OA patients than in controls and showed good diagnostic value for OA. Inhibiting miR-409-5p suppressed IL-1β-induced viability in CHON-001 cells, promoted aggrecan expression, suppressed MMP13 expression, and reduced secretion of IL-6 and IL-8. MiR-409-5p directly targeted DLST, and their expression levels were negatively correlated. Knockdown of DLST abolished the beneficial effects of miR-409-5p inhibition on cell viability, extracellular matrix degradation, and inflammatory responses. Conclusions MiR-409-5p was highly expressed in OA and may promote disease progression by targeting DLST
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