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Acute coronary syndrome (ACS) is a time-critical medical emergency in which early guideline-based prehospital diagnosis and treatment are crucial for the subsequent care pathway. The aim of this study was to compare documented adherence to selected prehospital ACS process indicators between two provider structures operating within the same municipal EMS system. As part of the retrospective, bicentric observational study MONAH-1, all prehospital physician missions with typical ACS diagnoses in Magdeburg between 2014 and 2018 were analysed. This prespecified intra-urban subgroup analysis compared one EMS physician base staffed by MD1 with two EMS physician bases staffed by MD2. Because case retrieval was diagnosis-targeted from archived protocols rather than based on a prospectively maintained screening registry, a full flow diagram of all EMS missions could not be reconstructed reliably; endpoint-specific denominators are therefore reported in the text and tables. Multivariable analyses were adjusted for age and gender only and should be interpreted as partially adjusted exploratory models. A total of 1,438 emergency physician interventions were evaluated (MD1: n&#x2009;=&#x2009;661; MD2: n&#x2009;=&#x2009;777). MD1 showed documented higher rates of 12-lead ECGs (76.9% vs. 43.5%; aOR 4.24 [95% CI 3.36-5.35]), ASA administration (91.4% vs. 70.9%; aOR 4.38 [3.19-6.00]) and heparin administration (92.6% vs. 68.0%; aOR 5.86 [4.21-8.16]). In the descriptive indication-positive subgroup with documented VAS&#x2009;&#x2265;&#x2009;4, morphine was documented more often at MD1 (70.6% vs. 54.5%); the exploratory adjusted morphine model was based on missions with documented pain assessment (aOR 2.67 [2.04-3.50]). No significant differences were found for indication-based nitro-glycerine and oxygen administration. Prehospital dwell time was longer at MD1 (median 34 vs. 29&#xa0;min; p&#x2009;<&#x2009;0.001). Documented adherence to selected prehospital ACS process indicators differed between the two providers. MD1 showed higher documented rates for several process measures, but the retrospective design, heterogeneous documentation formats, limited case-mix adjustment, and the possibility of reverse causation for dwell time preclude causal inference or conclusions about patient benefit. The findings are hypothesis-generating and primarily relevant for local quality assurance and prospective validation. The study was registered retrospectively in the German Clinical Trials Register (DRKS00036944) on 27 August 2025.

Recent neutral randomized controlled trials have created clinical equipoise around the treatment of obstructive sleep apnea (OSA) for the secondary prevention of cardiovascular disease. These findings are in part limited by poor compliance, lack of treatment optimization and personalization strategies with OSA therapy. This pilot study aims to assess the feasibility and impact of a personalized OSA treatment program on therapy compliance and cardiovascular health in patients with acute coronary syndrome (ACS) diagnosed with OSA. Patients with ACS and OSA (oxygen desaturation index 3%&#x2009;>&#x2009;10 events/hour) will be recruited and randomized to receive either personalized OSA therapy (PT) or usual care (UC) with six-month follow-up. The PT group will receive standard medical care for ACS plus the choice of continuous positive airway pressure and/or mandibular advancement device therapy for OSA. Treatment optimization strategies including treatment acclimatization, augmented support and patient engagement tools will be implemented. The UC group will receive standard medical care for ACS but no treatment for OSA. The primary outcome is the feasibility of personalized treatment for OSA assessed by study and treatment acceptance, and treatment compliance. Secondary outcomes include treatment effectiveness, cardiovascular health markers and patient reported outcomes across the six-months intervention. This study will provide novel findings on the impact of personalized and optimized OSA therapy on patient compliance, preliminary treatment effectiveness and health outcomes in patients with established cardiovascular disease. Such novel data will inform the design and delivery of future large scale randomized clinical trials to assess cardiovascular disease benefit in patients with OSA. ACTRN 12620000050954. Registered 22 January 2020, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378536&isReview=true.

Dental caries is among the most prevalent infectious chronic diseases worldwide, yet localized acidogenic activity associated with cariogenic processes often remains difficult to visualize at the whole-dentition level. This highlights the urgent need for analytical tools that enable imaging of localized acidity-related changes. However, current methods, such as salivary test strips and hand-held pH meters, remain limited to single-point or averaged measurements, lacking the spatial resolution required to visualize the distribution of acidic microenvironments. Herein, we present a conceptual approach that moves from single-point sensing to spatially resolved imaging through an AI-enhanced optical imaging platform for visualizing tooth-surface acidity patterns. The method integrates an imprint-based colorimetric assay using a food-derived pH indicator, with an AI-assisted image analysis workflow guided by dentist-labeled annotations, and explores the feasibility of supervised, annotation-guided image analysis under pilot conditions. By mapping localized acidogenic activity as an indicator associated with cariogenic bacteria, the method provides interpretable spatial readouts of acidic microenvironments. The method allows visual detection of lactic acid at concentrations as low as 5 mM under the tested conditions, and provides multisite results within 5 min, showing qualitative spatial correspondence with clinical findings within this pilot cohort. This approach demonstrates the initial feasibility of treating the dentition as an analytically accessible surface, and explores an AI-assisted analytical concept for relating spatial pH patterns to clinician-identified caries-associated regions on biological surfaces. By combining accessible materials with intelligent data interpretation, this study presents a proof-of-concept pathway toward low-cost visualization of microenvironments for at-home and low-resource settings, offering particular value for children, the elderly, and individuals in remote areas.

Bacterial infection is now a significant obstacle to the effective repair and regeneration of both soft tissues and bone in clinical settings. Managing infected sites is challenging due to multiple antimicrobial resistance, abnormal inflammatory responses, and an excessive inflammatory microenvironment. To meet the complex healing needs following soft tissue or bone, an immunomodulatory thermosensitive hydrogel was designed and synthesized. The composite hydrogel (CQDs@UPDA@gel) combines carbon quantum dots (CQDs) as the second near-infrared window (NIR-II) photothermal agents (PTAs) and ultrasmall polydopamine nanoparticles (UPDA NPs) as reactive oxygen species (ROS) scavengers and immunomodulators, embedded within a chitosan matrix coordinated with Cu2+ that enhances the good swelling performance and stable rheological properties of the hydrogel. This synergistic approach simultaneously inhibits bacterial infection and alters the immunosuppressive microenvironment, thereby promoting coordinated soft tissue or bone regeneration. In vivo studies have shown that the hydrogel can encourage the regeneration of soft tissue or bone under NIR-II laser irradiation for the treatment of infectious wounds, subcutaneous abscesses, and infectious bone defects in the maxillofacial region. Overall, this project offers a general strategy for creating multifunctional hydrogels that both eradicate pathogens and modulate the immune microenvironment to support the repair of complex soft tissue or bone infections.

Early and accurate diagnosis of Chikungunya virus (CHIKV) infection is critical for controlling its outbreaks. CRISPR/Cas-based detection offers promise for pathogen identification, yet one-step CRISPR/Cas systems are limited by suboptimal sensitivity, field-deployability, and adaptability to complex clinical samples, hindering their use in rapid outbreak response. Here, we developed a CRISPR/Cas13a-based One-Step System for Rapid Detection of Emerging Viruses (CRISPR-CORE) and applied it during the CHIKV outbreak in Guangdong Province, China. Multidimensional optimizations enabled the CRISPR-CORE system to achieve a limit of detection of 5 copies/&#x3bc;L within 40 min. An extraction-free RNA release protocol for CHIKV in blood samples and a premixed reagent approach were implemented. Furthermore, a portable fluorescence detector was used to enhance user-friendliness in point-of-care (POC) settings. The clinical CHIKV genomic information was identified through hybrid capture sequencing, informing the design of highly specific CRISPR RNA (crRNA). Clinical validation across three regions yielded 92.6% sensitivity and 100% specificity, underscoring the applicability and reliability of the CRISPR-CORE system. Our system demonstrates its suitability for CHIKV outbreak detection. It facilitates rapid and POC testing for emerging viruses in resource-limited settings. Furthermore, it provides a universal strategy for the prevention and control of infectious diseases.

To describe the epidemiology of local signs at intravascular catheter insertion sites across catheter types and care settings, to compare the identification of redness between local investigators and experts, and to evaluate the association between redness and blood culture positivity in patients with suspected infection. DeepCath was a prospective multicentre cohort study conducted between September 2022 and December 2023 in France and Switzerland. Adult patients with short-term central venous catheters (CVCs), arterial catheters (ACs), peripheral venous catheters (PVCs), peripherally inserted central catheters (PICCs), or midlines were included. Local investigators captured one photograph per insertion site and recorded local signs. Four experts independently reassessed all images, serving as the reference standard. Agreement between local investigators and experts on redness was evaluated using Cohen's kappa. Among patients with suspected infection, the association between redness and blood culture results was evaluated. Among 5,164 collected images, 2,670 eligible catheters (one image per catheter) were analysed: 1,447 PVCs (54.2%), 608 CVCs (22.8%), 296 ACs (11.1%), and 319 PICCs/midlines (11.9%). Local investigators reported signs of local infection in 257/2,670 catheters (9.6%), mainly redness (218/2,670, 8.2%). Experts identified local infection signs in 376/2,670 catheters (14.1%), including redness in 364/2,670 (13.6%). Redness prevalence varied by catheter type and was highest for PICCs/midlines (82/319, 25.7% by expert assessment). Overall agreement for redness was fair (Cohen's kappa of 0.40, 95% CI 0.35-0.46) and was observed in 2,358/2,670 images (88.3%). Among 732 patients with suspected infection who underwent blood cultures diagnostic, redness was more frequent in those with positive cultures (23/71, 32.4%) than in those with negative (15/225, 6.7%) or pending cultures (40/436, 9.2%; p<0.0001). Local signs at catheter insertion sites are frequent and differ across catheter type. Redness is under-recognised in routine clinical assessment compared with expert review, supporting the need for standardized, potentially artificial intelligence-assisted, approaches in daily practice.

Lipid mediators can control the inflammatory response in infectious diseases, including leishmaniasis. However, these mediators may promote antagonistic roles in the Leishmania-host interaction depending on the species involved in the infection. Herein, we analyzed the role of mediators in the Leishmania-host interaction in the experimental and clinical context, aiming to identify the main cell types studied, as well as the main eicosanoids and their influence during the infection. The main lipid mediators studied were the eicosanoids LTB4 and PGE2, which are related to the inflammatory response in cutaneous and visceral leishmaniasis. In vitro models using macrophages and neutrophils infection reveal that LTB4 plays a fundamental role in reducing the parasite load, while PGE2 and PGF2&#x3b1; suppress the immune response, favoring the survival of the parasite in the host. In the in vivo infection, PGE2 is related to the visceralization process of the disease and the persistence of tegumentary lesions. An emerging role in pathophysiology has been pointed out for the mediators of the HETE class and for Resolvin D1, which act favoring Leishmania infection and are associated with more severe cases of the disease. Thus, it can be concluded that lipid mediators play crucial roles in the Leishmania-host interaction, modulating the inflammatory response and disease progression. Studies exploring the contribution of intervention in the production of lipid mediators during the course of the disease are still needed.

Indole 4-carboxamides are promising prodrugs that liberate 4-aminoindole, which poisons tryptophan biosynthesis in Mycobacterium tuberculosis (Mtb). Limiting enthusiasm for these compounds is the high rate of emergence of resistance since the amidase, which liberates the 4-aminoindole core, is nonessential. To overcome this limitation, we designed bifunctional &#x3b2;-lactams that, upon hydrolytic opening of the &#x3b2;-lactam ring, liberate 4-aminoindole. These bifunctional molecules had good potency against Mtb, which could be rescued by exogenous l-tryptophan addition. In contrast to the parental indole 4-carboxamides, resistant mutants to these bifunctional compounds developed at a much lower frequency than the parental compounds in vitro, supporting this strategy as a means to protect these agents from rapid development of resistance.

The assembly of enveloped viruses is a highly orchestrated process that depends on the coupling of multiple protein-protein interactions within a membrane environment. To gain mechanistic insight into this process, we use Chikungunya virus as a model system to study Alphavirus assembly, focusing on the interplay between core-spike and spike-spike interactions. We begin with coarse-grained molecular dynamics simulations to systematically explore how the symmetry of the nucleocapsid core, together with the relative strengths of spike-core and spike-spike interactions, influences budding efficiency and the emergence of icosahedral particle symmetry. Building on these computational results, we performed site-directed mutagenesis on Chikungunya virus 181/25 and examined the consequences for particle assembly and budding in cultured cells, as well as the impact of these mutations during in-cellulo assembly. Our results revealed that canonical core-spike interactions, while necessary, were not sufficient for successful assembly. Instead, lateral interactions among glycoproteins emerged as critical determinants of efficient budding, particle stability, and the maintenance of icosahedral symmetry. Together, these findings provided an integrated computational and experimental framework for understanding the molecular principles governing Alphavirus assembly.

Antimicrobial resistance represents a critical global health challenge, necessitating deeper insights into bacterial regulatory networks that govern adaptive survival and can be exploited as novel targets for drug discovery. Among these, nucleotide-based second messengers have emerged as central modulators of bacterial physiology and stress responses. Cyclic dinucleotides, including c-di-GMP and c-di-AMP, alongside the alarmone (p)ppGpp, orchestrate diverse cellular processes required for bacterial survival, pathogenesis, and metabolic regulation. Accumulating evidence highlights their pivotal role in shaping antimicrobial susceptibility through biofilm formation, transcriptional regulation, influencing target accessibility, efflux pump expression, persistence, and tolerance phenotypes. Dysregulation of these signaling pathways could promote the evolution of resistance, either directly or indirectly, by modulating fitness landscapes and stress-induced mutagenesis. This review summarizes the current knowledge of global regulators (c-di-GMP, c-di-AMP, and (p)ppGpp) with respect to their contributions in governing AMR in priority pathogens, emphasizing their potential as promising targets for novel antimicrobial and antibiofilm strategies.

With zoonotic outbreaks on the rise, rapid and accurate infectious disease diagnostics are critical for both human and animal health. Traditional lateral flow assays lack sensitivity and specificity, while isothermal amplification methods like LAMP, though rapid, can be hindered by optical detection issues. We present an electrochemical nucleic acid amplification test (NAAT) that combines isothermal amplification with real-time voltammetric detection. This novel method relies on monitoring of amplification-associated proton release through redox probing of a pH-sensing compound. The method shows high concordance with RT-qPCR under the tested conditions and demonstrates a limit of detection (LOD) of 50 copies/reaction for IAV. In RNA purified from clinical samples, 231/234 (98.7%) are concordant with RT-qPCR for SARS-CoV-2, IAV, IBV, or RSV A. In a proof-of-concept extraction-free workflow, 14/14 equine nasal swab samples are correctly classified for EHV-5 relative to qPCR. Together, these data support the feasibility of real-time voltammetric LAMP across several sample types, while broader point-of-care validation across additional matrices and prospective cohorts remains to be established.

In Pseudomonas aeruginosa, bacterioferritin contributes to regulating cytosolic iron by oxidizing Fe2+ and storing Fe3+ within its internal cavity, and binding to its cognate ferredoxin to reduce stored Fe3+ and release Fe2+ to the cytosol. Small molecule derivatives of 4-aminoisoindoline-1,3-dione bind P. aeruginosa bacterioferritin at the cognate ferredoxin binding site, inhibit iron release from bacterioferritin, and exhibit bactericidal activity against mature P. aeruginosa biofilms. In this study we report that treatment of mature biofilms with the 4-aminoisoindoline-1,3-dione derivative KM-5-35 induced approximately 90% cell death. Proteomic analysis of surviving cells revealed iron limitation accompanied by disrupted central carbon metabolism, reduced fatty acid and amino acid biosynthesis, and alterations in ribosome protein composition. These metabolic downshifts likely resulted in unstable proton motive force, diminished efflux capacity and impaired ribosome turnover. In this compromised state, gentamicin and amikacin, but not tobramycin, efficiently exploit KM-5-35-induced translational stress, leading to profound synergistic killing of biofilm cells. These findings underscore the therapeutic potential of targeting bacterioferritin iron mobilization in biofilm-associated infections and suggest a promising strategy for combination antimicrobial therapy.

Gonorrhea, caused by Neisseria gonorrhoeae, is a widespread sexually transmitted disease that is becoming resistant to all currently used antibiotics. Therefore, new therapeutics for gonorrhea are desperately needed. Here, we show that a natural product, aerocavin, is highly potent and specific against Neisseria. Aerocavin accumulates in N. gonorrhoeae at high levels and inhibits bacterial RNA polymerase (RNAP) by binding the switch region. Aerocavin resistance mutations evolve in N. gonorrhoeae at a low rate and are absent in clinical isolates. Previously overlooked narrow-spectrum antimicrobials like aerocavin may enable microbiome-sparing treatments of gonorrhea.

To gain molecular-level insights into cisplatin and its metal analogs, we performed a comprehensive investigation of the geometric and electronic structures of cis-[M-(NH3)2Cl2] (M = CoI, RhI, IrI, NiII, PdII, PtII, CuIII, AgIII, and AuIII), along with their bonding characteristics and hydrolysis behaviors. All complexes adopt a planar, four-coordinate geometry, with the d x 2 - y 2 orbital predominantly involved in ligand interactions. EDA-NOCV analyses indicate that the total interaction energy increasing from Group 9 to 11 with &#x3c3;-interactions dominates the metal-ligand bonding. cis-[M-(NH3)2Cl2] with M = CoI, RhI, and IrI were found to be unstable, exhibiting a tendency to form five-coordinated species. In contrast, cis-[M-(NH3)2Cl2] complexes (M = NiII, PdII, PtII, CuIII, AgIII, and AuIII) undergo ligand exchange reactions via penta-coordinate trigonal-bipyramidal-like transition states. Their monoaquated derivatives all demonstrated high reactivity toward guanine. Considering their hydrolysis behaviors, cis-[AuIII(NH3)2Cl2]+ emerges as a potential candidate for antitumor applications.

Bacterial cells are surrounded by a dynamic cell wall which is made up of a mesh-like peptidoglycan (PG) layer that provides the cell with structural integrity and resilience. In Gram-positive bacteria, this layer is thick and robust, whereas in Gram-negative bacteria, it is thinner and flexible as the cell is supported by an additional outer membrane. PG undergoes continuous turnover, with degradation products being recycled to maintain cell wall homeostasis. Some Gram-negative species can bypass de novo PG biosynthesis, relying instead on PG recycling to sustain growth and division. Legionella pneumophila (hereafter Legionella), the causative agent of Legionnaires' disease, encodes such recycling machinery within its genome. This study investigates the biochemical, genetic, and pathogenic roles of PG recycling in Legionella. Here, two PG recycling gene homologues in the Legionella genome lpg0296 (amgK) and lpg0295 (murU) were identified; chemical biology strategies were used to illuminate incorporation of "click"-PG-probes into whole PG. Copper-free click chemistry with ultrafast tetrazine-NAM probes enabled live-cell PG labeling further supported the use of recycling programs in Legionella. Deletion of amgK abolished PG labeling, while genetic complementation restored labeling. The data suggest that under conditions where de novo peptidoglycan synthesis is blocked, amgK plays a critical role in maintaining cell wall integrity, as its deletion led to increased antibiotic susceptibility and impaired survival in host alveolar macrophages. An intracellular survival assay demonstrated that while PG recycling is not essential for internalization, survival of Legionella within MH-S murine alveolar macrophages requires functional amgK. These findings underscore the essential role of AmgK in Legionella's intracellular survival, emphasizing the importance of PG recycling in pathogenicity, and establishing a foundation for developing novel Legionella-specific antibiotic strategies.

Mutations in the fusA gene are crucial pathways for high-level aminoglycoside resistance, creating a major barrier to treating chronic cystic fibrosis (CF) lung infections. While lab models often failed to replicate the translational gap seen in advanced clinical strains, we found that metabolic dormancy, rather than physical biofilm structure, was the key survival strategy in CF isolates. To address this, we introduced AuNC@ATP, a gold nanocluster platform that acted as an evolutionary adjuvant. AuNC@ATP remained highly effective against bacteria in serum-rich environments, where traditional nanomaterials usually failed. Importantly, whole-genome profiling revealed that AuNC@ATP constrained adaptive mutational trajectories. While tobramycin monotherapy was selected for fusA-associated adaptation, AuNC@ATP co-treatment suppressed the emergence of fusA mutations, and no transversion events were detected in the co-treatment lineage. By trapping pathogens in a sub-optimal genetic state, AuNC@ATP offered a dual-action strategy that provided immediate clinical benefits while maintaining the long-term usefulness of existing antibiotics.

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Reactive arthritis induced by Mycobacterium tuberculosis (M.tb) causes severe cartilage degradation, yet the underlying mechanisms remain elusive. This study investigated the molecular mechanisms and potential therapeutic targets for M.tb-induced cartilage damage. A mouse model of BCG-induced tuberculous arthritis was established. Cartilage matrix degradation, chondrocyte apoptosis, and metabolic balance were evaluated histologically and biochemically. Activation of the NF-&#x3ba;B p65 and STAT3 signaling pathways was assessed, followed by pharmacological inhibition. BCG infection significantly reduced cartilage matrix content and promoted chondrocyte apoptosis, disrupting the metabolic balance between matrix synthesis and degradation. Mechanistically, BCG markedly activated the NF-&#x3ba;B p65 and STAT3 pathways in articular cartilage. Pharmacological inhibition of these pathways effectively prevented cartilage matrix loss and reduced chondrocyte apoptosis at the protein level. BCG induces cartilage damage through activation of NF-&#x3ba;B p65 and STAT3 pathways, leading to chondrocyte apoptosis and matrix catabolism. Targeting these signaling cascades represents a promising therapeutic strategy for preventing cartilage degeneration in tuberculous arthritis.

Emerging evidence indicates that pyroptosis contributes to neuroinflammation and central nervous system (CNS) injuries. However, its role in Streptococcus suis (S. suis)-induced brain damage remains unclear. Here, we demonstrate that S. suis strain P1/7 infection triggers pyroptosis in astrocytes, specifically characterized by activating NLRP3/caspase-1/GSDMD axis. Suilysin (SLY), a key virulence factor of S. suis, dose- and time-dependently induced pyroptosis in U251 cells. Notably, genetic ablation of NLRP3 or GSDMD significantly attenuated SLY-induced pyroptosis, and caspase-1 inhibition similarly suppressed this process. Furthermore, SLY promoted reactive oxygen species (ROS) production, and scavenging ROS inhibited NLRP3/caspase-1/GSDMD activation and pyroptosis. Consistently, in a murine infection model, S. suis P1/7 induced astrocyte pyroptosis in brain tissues, while its sly deleted mutant (P1/7-&#x394;sly) significantly reduced this effect. These findings reveal that SLY mediates pyroptosis in astrocytes via the ROS/NLRP3/caspase-1/GSDMD pathway, highlighting its critical role in S. suis-induced neuropathogenesis.