Intravitreal (IVT) administration of adeno-associated virus (AAV) vectors is considered a promising strategy for retinal gene therapy. Random peptide-display-based directed evolution has yielded novel AAV capsids with potent retinal bioactivity. However, recent reports on safety risks following IVT AAV administration indicate that significant opportunities remain to further refine AAV vector technology. Here, we performed iterative in vivo NGS-guided screening of AAV2 peptide-display libraries in both mice and non-human primates (NHPs), integrating barcoded functional analytics, and single-nuclei RNA sequencing to identify retina-tropic AAV variants. The top-performing capsid in mice, AAV2-GAYPKSP robustly drove eGFP expression in a human retina-on-chip model but failed to drive gene expression in the NHP retina following IVT delivery. In NHPs, a barcoded evaluation of 70 retina-tropic variants revealed a complex correlation between viral genome enrichment and transgene transcriptional output, providing insights that enhance the mechanistic interpretation and methodological design of AAV library selection strategies. Nonetheless, several NHP variants, including AAV2-I.1 and AAV2-I.12, demonstrated broad retinal transduction and potent expression, outperforming benchmarks AAV2 and AAV2-7m8. Single-nucleus RNA sequencing confirmed broad cell-type tropism of the top performing variants. Collectively, these findings expand the AAV toolkit for retinal gene therapy and underscore the importance of optimized screening methodologies in vector discovery.
Salmonella remains one of the most critical zoonotic pathogens in the poultry sector, linked to animal disease, foodborne illness, and the global crisis of antimicrobial resistance (AMR). Poultry acts as a major reservoir, enabling Salmonella transmission from hatchery to retail products through horizontal, vertical, and environmental routes. Despite the use of biosecurity, vaccination, antibiotics, and chemical decontamination, effective and sustainable control across the poultry value chain remains difficult, particularly in the face of rising multidrug-resistant strains and growing consumer concerns over chemical residues. Bacteriophages (phages), viruses that selectively infect and lyse bacteria, have emerged as a promising biological alternative for Salmonella control. Although many studies have reported the effectiveness of phages against bacterial species, including Salmonella, in the poultry industry, reports on their full potential to combat antimicrobial-resistant Salmonella across the entire poultry value chain remain limited. Therefore, this review synthesizes current evidence on the application of phages throughout the poultry value chain, including on-farm interventions, processing plant decontamination, and food packaging and storage. Findings from the reviewed articles indicate over a 90% reduction in Salmonella spp. in poultry farms and post-harvest meat, along with lower mortality in phage-treated groups compared to untreated groups; however, these outcomes depend on several factors (e.g., phage strains, concentrations, application methods, and environmental conditions). Laboratory, pilot, and field studies consistently demonstrate that phage preparations, especially when formulated as cocktails or combined with complementary interventions, can achieve substantial reductions in Salmonella, including antibiotic-resistant serovars, in live birds, eggs, poultry environments, and meat products. Unlike antibiotics and chemical sanitizers, phages act with high specificity, preserving beneficial microbiota and maintaining the sensory and nutritional quality of poultry products. Their safety has been supported by toxicological and genomic assessments, and several phage-based products have obtained regulatory approval, including Generally Recognized as Safe (GRAS) status for food applications in the United States. By integrating efficacy, safety, regulatory, and practical deployment data, this review highlights bacteriophages as a scientifically validated and One Health-aligned tool capable of reducing Salmonella transmission from farm to fork across the poultry value chain, thereby laying the foundation for their future adoption in the poultry industry. Phage-based interventions offer a sustainable pathway to enhance food safety, limit antimicrobial resistance (AMR) dissemination, and strengthen consumer confidence in poultry products. However, the major limitation is the emergence of phage-resistant bacterial strains, as well as the potential involvement of some phages in the transfer of resistance and virulence genes, which could raise public concern. Nevertheless, the use of phage cocktails and whole-genome sequencing, involving tools such as ResFinder and virulence finder, can facilitate the selection of safe phages for application.
Immunoglobulin A (IgA) nephropathy (IgAN) with superimposed minimal change disease (MCD) is a rare but increasingly recognized clinicopathological phenotype that is generally associated with a favorable renal prognosis. We present a case of IgAN with MCD complicated by severe acute kidney injury (AKI) during the clinical course and requiring temporary renal replacement therapy. A 38-year-old man presented with acute nephrotic syndrome. Renal biopsy showed mesangial IgA deposition, and anti-galactose-deficient IgA1 antibody (KM55) staining demonstrated co-localization with IgA deposits, supporting the diagnosis of IgAN with superimposed MCD. Electron microscopy revealed foot process effacement, leading to a diagnosis of IgAN with MCD. High-dose prednisolone therapy was initiated; however, the patient subsequently developed severe AKI requiring hemodialysis (HD). Concurrent treatment with cyclosporine A and steroid pulse therapy was administered, ultimately allowing successful discontinuation of HD. This rare case was diagnosed as IgAN with MCD based on mesangial IgA deposition supported by KM55 staining and characteristic electron microscopic findings, and this case demonstrates that severe AKI requiring temporary HD may occur during the clinical course of IgAN with MCD. Although IgAN with MCD has been increasingly recognized, reports of cases complicated by severe AKI requiring HD remain limited in the literature. This patient showed subsequent improvements in renal function and proteinuria, suggesting that this condition may be reversible. These findings highlight the importance of careful clinical management with attention to the potential risk of AKI even in patients with IgAN with MCD.
Chimeric antigen receptor (CAR)-T cells represent a recent clinically validated modality in cancer therapy and beyond. However, broad industrial implementation faces technological, logistical, regulatory and financial challenges. A major bottleneck is the ex vivo production process, where cytokines are essential and product-determining constituents. To better understand the complexity of cytokine utilization throughout the production process, we rigorously reviewed the existing literature, including extended manufacturing parameters from 292 available clinical reports. We found a progressive reduction of interleukin-2 exposure, driven by its association with unfavourable cell characteristics. Preclinically, this catalysed the evaluation of alternative cytokines with potential to preserve naive phenotypes, support cell expansion and enhance the efficacy of CAR-T cells. Here we illustrate the evolving use of cytokines, reveal non-standardized clinical CAR-T cell manufacturing parameters, and summarize preclinical and next-generation concepts, which may improve manufacturing efficiency, cost-effectiveness and therapeutic outcomes. Our observations may further guide the development of cytokine-armouring strategies to promote in-patient expansion and persistence, even as innovations such as shortened manufacturing and in vivo engineering techniques could reduce reliance on cytokines during ex vivo culture.
Treatment strategies for patients with advanced melanoma resistant to adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) remain undefined. The efficacy of immune checkpoint inhibitors (ICIs) after TIL has not been previously described. Patients with unresectable melanoma who received ICI therapy both before and after TIL treatment were retrospectively identified at 14 international centers. Safety was evaluated among all patients that received one dose of ICI therapy after TIL. Objective response rates (ORR) were determined based on investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 responses based on radiology reports. Kaplan-Meier methodology was used to estimate overall survival (OS) and melanoma-specific survival. Among 133 patients assessed for response to ICI therapy after progression on TIL therapy, the ORR was 11% (n=14; 95% CI 5.9% to 17%), including 3 complete responses (2.3%) and 11 partial responses (8.3%). Among patients treated with a programmed death-1 inhibitor prior to TIL (n=121), the ORR was 8.3% (95% CI 4.0% to 15%). At a median follow-up among survivors of 21 months, median OS from post-TIL ICI was 8.8 months (95% CI 6.5 to 12 months). Among 14 patients with response to post-TIL ICI, 13 received an ICI they had not previously received. In the safety cohort (n=138), post-TIL ICI therapy-related toxicity occurred in 31 patients(22%), among which 7 patients (5.1%) experienced recurrence of an adverse event experienced with prior ICI treatment. Efficacy with ICI after TIL was limited, with no evidence of synergistic toxicity. As TIL therapy becomes more widely available, these data highlight the need for novel therapies in this setting and support the inclusion of this population in future clinical trials.
Genome-based bacterial taxonomy requires standardized and reproducible analytical workflows for species delineation and phylogenomic placement; however, the practical deployment of these workflows remains a significant barrier for experimental biologists and clinical scientists. Widely adopted tools such as Prokka, antiSMASH, and PhyloPhlAn underpin key steps in genome annotation, functional characterization, and phylogenomic reconstruction, but their practical deployment in routine laboratory settings, especially on Windows based systems, remains non trivial due to complex software dependencies and command line centric workflows. Existing solutions, including cloud-based platforms (e.g., Galaxy and KBase) and commercial software suites (e.g., CLC Genomics Workbench), partially alleviate these challenges but may also involve considerations related to data-privacy concerns, upload latency, storage quotas, shared computing resources, and recurring licensing costs. To address these limitations, we introduce TaxaScope, a graphical-interface-driven desktop workstation designed to support reproducible, genome-based bacterial taxonomy by integrating a curated set of community-validated tools for genome quality assessment, annotation, phylogenomic inference, genome relatedness estimation, and functional profiling within a unified local graphical user interface (GUI). By leveraging Docker- and Podman-based containerization behind a user-friendly frontend, TaxaScope provides version-locked, standardized execution environments across computing platforms without requiring manual dependency management or prior Linux expertise. We demonstrate the utility of TaxaScope through a comprehensive re-analysis of Pseudomonas putida KCTC 1751T, illustrating how standardized taxonomic workflows can be executed locally while automatically generating high-quality circular genome maps and interactive functional reports suitable for downstream interpretation and figure preparation directly from native tool outputs. Collectively, TaxaScope lowers the technical barrier to standardized and reproducible genome-based bacterial taxonomy by providing a private, locally controlled, containerized workflow that complements cloud-based and commercial infrastructures for routine taxonomic research. By providing a containerized and visualization-oriented desktop environment, TaxaScope facilitates the standardized execution of established genomic tools, thereby bridging the gap between complex bioinformatic workflows and consistent bacterial taxonomy.
Polyphenol-rich pomegranate extract has been shown to inhibit microbial trimethylamine (TMA) production from L-carnitine. Previous clinical studies have examined effects of polyphenol-rich interventions on fasting trimethylamine N-oxide (TMAO) concentrations but have not assessed pharmacokinetic TMAO responses following an oral carnitine challenge (OCC). We investigated whether a single dose of pomegranate extract attenuates the plasma TMAO response to an OCC in healthy adults. This two-phase dietary intervention study enrolled 34 healthy, omnivorous adults. In Phase I, participants completed an OCC (1.5 g L-carnitine) to identify high TMAO producers (increase ≥ 5 μmol/L). Twenty high producers entered Phase II; an 18-day double-blind, randomized, placebo-controlled, crossover study with two 48-h pharmacokinetic interventions separated by a 10-day washout. Interventions consisted of an OCC with concurrent pomegranate extract (1.6 g) or placebo. Each OCC was preceded by a 48-h low-TMAO precursor run-in diet. Participants arrived fasted (>8 h), and all meals during the intervention periods were fully standardized to minimize dietary variability. Blood, urine, and stool samples were collected, and TMAO was quantified using LC-MS/MS. Differences in TMAO area under the curve (AUC) were analyzed using linear mixed-effects models. Ninety one percent of participants meeting the Phase I inclusion criteria produced substantial TMAO quantities from L-carnitine. This proportion exceeds that of earlier reports. Pomegranate extract did not reduce TMAO AUC in the full Phase II cohort (placebo/pomegranate ratio 0.993, 95% CI 0.81-1.22; P = 0.945; n = 16). However, a post hoc subgroup analysis showed that the effect of the pomegranate extract on plasma TMAO differed by age and sex. Under tightly controlled dietary conditions, a single dose of pomegranate extract did not reduce post-OCC TMAO responses in the overall cohort. Post hoc analyses suggest potential sex- and age-dependent effects, warranting confirmation in larger, adequately powered studies. https://clinicaltrials.gov/, identifier NCT06518343.
Bloodstream infections (BSIs) remain a major cause of morbidity and mortality worldwide and continue to represent a substantial challenge to modern healthcare systems. These infections arise when pathogenic microorganisms gain access to the bloodstream, triggering systemic inflammatory responses that may progress to sepsis, septic shock, multi-organ dysfunction, and death. This review provides a comprehensive overview of the historical development, epidemiology, pathogenesis, diagnosis, treatment, and future perspectives of BSIs. The major bacterial, fungal, viral, and parasitic pathogens associated with BSIs are discussed, with particular emphasis on their virulence attributes, mechanisms of immune evasion, antimicrobial resistance, and clinical significance. A comprehensive literature review was conducted using peer-reviewed publications, clinical guidelines, surveillance reports, and systematic reviews published between 2010 and mid-2026. Evidence related to bacterial, fungal, viral, and parasitic bloodstream pathogens, host-pathogen interactions, diagnostic modalities, antimicrobial resistance mechanisms, and emerging therapeutic and diagnostic innovations was critically evaluated and integrated. BSIs continue to impose a substantial healthcare burden, driven by increasing antimicrobial resistance, delayed diagnosis, and diverse pathogen-specific virulence mechanisms. Bacterial pathogens remain the predominant cause of BSIs, whereas Candida species represent the leading fungal agents. Advances in molecular diagnostics, metagenomic sequencing, biomarker-guided testing, and artificial intelligence-assisted analyses have substantially improved rapid pathogen detection and therapeutic decision-making. Precision medicine, genomic surveillance, and novel antimicrobial agents show considerable promise for enhancing clinical management and addressing multidrug-resistant infections. Bloodstream infections remain a major global health challenge due to their complex pathogenesis, increasing antimicrobial resistance, and high associated mortality. Improving patient outcomes requires early and accurate pathogen identification, prompt initiation of targeted antimicrobial therapy, effective antimicrobial stewardship, and continuous epidemiological surveillance. The integration of next-generation diagnostics, artificial intelligence-assisted pathogen detection, genomic surveillance, and precision medicine has the potential to transform BSI diagnosis and management by enabling rapid, individualized therapeutic interventions.
Diazepam (DZP) is a widely prescribed drug for central nervous system disorders. However, it also exhibits a significant inhibitory effect on tubulin and the mitotic kinesin Eg5. These novel mitotic mechanisms explain its cytotoxicity and provide valuable insights for designing safer, more targeted antimitotic agents. Studies in mammalian cancer and noncancerous cell lines, including HeLa, MCF-7, A549, and L929, demonstrated that DZP inhibits cell proliferation in a concentration-dependent manner, with IC50 values ranging from 42 μM to 76 μM. Fluorescence spectroscopy confirmed direct binding of DZP to tubulin and Eg5, with dissociation constants (Kd) of 33.6 μM and 50.5 μM, respectively. This binding disrupted GTPase activity of tubulin and ATPase activity of Eg5, both of which are essential for mitotic progression. Consequently, DZP caused microtubule disorganization, impaired centrosome separation, and induced monopolar spindle formation, collectively leading to mitotic arrest in various cancer cell lines as well as non-cancerous cells. Additionally, DZP induced mitochondrial membrane potential loss and apoptosis, while inhibiting cell migration and colony formation, highlighting its cytotoxic effects. Furthermore, DZP synergistically enhanced the mitotic inhibition induced by the antimitotic agent vinblastine, further suppressing cancer cell proliferation. The findings indicate that DZP exhibits a probable, multi-target antimitotic effect, involving interactions with both tubulin and Eg5, which suggests a need for careful evaluation of its biological safety window. This revised approach addresses concerns regarding the cytotoxic risks and potential antiproliferative effects of DZP in conventional anxiolytic applications.
Metastatic triple-negative breast cancer (TNBC) remains highly challenging to treat despite advances in oncology. This study investigated whether non-invasive alternating, low-intensity induced electric fields (iEFs) could suppress tumor growth and metastasis while modulating anti-tumor immunity in TNBC. Orthotopic TNBC mouse models were treated with alternating (100 kHz) and low-intensity (2.7 mV/cm peak), induced electric fields (iEFs), which were delivered non-invasively via a solenoid coil system. Tumor growth and lung metastasis were assessed following treatment. Immune profiling was performed to evaluate changes in T cell states and myeloid cell populations within both primary tumors and metastatic lung tissue. iEF treatment significantly reduced primary tumor growth (n=9) and lung metastases (n=5). Within the tumor microenvironment, iEFs decreased infiltration of immunosuppressive myeloid cells (n=8). In the lung metastatic niche, iEF therapy increased CD8+ T cell abundance while reducing immunosuppressive myeloid populations (n=8). We also observed that iEFs reduced the metastatic potential of cancer cells by inhibiting epithelial-to-mesenchymal transition (n=3). Induced electric field therapy enhances anti-tumor immunity and suppresses metastatic progression in TNBC by enhancing T cell activity and remodeling immunosuppressive myeloid environments. These findings support iEFs as a promising non-invasive immunomodulatory strategy for metastatic TNBC.
The heavy metal lead (Pb) is widely accepted as a toxicant that impairs different physiological functions dependent on dose. The central nervous system (CNS) is highly sensitive to Pb especially when exposure occurs during early developmental periods. Moreover, even low Pb exposures during development can be detrimental and have long-lasting effects on the individual. Pb has also been implicated to exert changes across generations, impairing physiological traits as well as behavioral markers exerting an impairment in the health span. In this study, the developmental effect of environmental-relevant concentrations of Pb (0.01, 0.1, and 1 ppb; μg/L) were assessed in the F1 (multigenerational) and F2 (transgenerational) generations from an F0-exposed zebrafish (Danio rerio). Behavioral, oxidative, and lipid-profiling were assessed for these generations to identify changes inherited from developmental Pb contact. Behavioral assessments revealed an embryonic Pb exposure in the F0 generation led to significant hypolocomotion, anxiolytic- and anxiogenic-like behaviors, impaired social interaction, and reduced decision-making capacity in F1 larvae. On the other hand, minimal effects were observed in the F2 larvae. Lipidomic analysis indicated these behavioral phenotypes were associated with altered levels of sphingomyelins, phosphatidylcholines, and cholesterol esters, suggesting disrupted neuronal signaling and membrane homeostasis. Enzymatic alterations were related to glutathione metabolism and those might be driven by some mechanistic Pb-induced epigenetic modifications. Together, these findings provide evidence that low-level Pb exposure induces multigenerational neurobehavioral toxicity, mediated by lipidomic and redox pathway disruptions, with implications for long-term environmental health risk assessment.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord, with mutant superoxide dismutase 1 (SOD1) induced oxidative stress and neuroinflammation as key pathogenic drivers. Here, we uncover that mutant SOD1 is both a Fenton-like agent able for catalytical generation of ·OH and a hydrogenation catalyst for H2 scavenging reactive oxygen species. To enhance the bioavailability of H2, we develop an orally administered Mg2Si nanosheets based feed for sustained release of high-amount H2. On an ALS model of hSOD1G93A transgenic mice, Mg2Si feed remarkably delays ALS progression, improves the motor performance of ALS mice, and extends their lifespan. Histopathologically, oral Mg2Si treatment ameliorates motor neuron degeneration, misfolded SOD1 aggregation and reactive gliosis in spinal cord, while protecting neuromuscular junctions and ameliorating muscle atrophy during disease progression. Transcriptomic analysis demonstrates the H2-mediated down-regulation of both oxidative stress and neuroinflammatory pathways in response to the suppression of NLRP3 inflammasome activation. The proposed strategy of catalyzed hydrogen therapy offers an inspiration for metalloproteases-related neurodegenerative diseases treatment. STATEMENT OF SIGNIFICANCE: Amyotrophic lateral sclerosis (ALS) is an incurable and devastating neurodegenerative disease lacking effective clinical interventions. Although hydrogen gas (H2) exhibits promising neuroprotective potential, conventional H2 therapy is severely limited by unstable and transient H2 release, failing to sustain long-term treatment requirements for chronic ALS pathogenesis. To overcome this bottleneck, we engineer oral administrable Mg2Si nanosheets that enable sustained H2 release via gastrointestinal retention, achieving stable long-term hydrogen supplementation in vivo. Mechanistically, Mg2Si-derived H2 efficiently eliminates excess free radicals triggered by toxic mutant SOD1, and further disrupts the pathological crosstalk between oxidative stress and neuroinflammation in ALS. In transgenic ALS mice, dietary Mg2Si intervention markedly ameliorates motor dysfunction and effectively delays disease progression. Collectively, this study firstly applies Mg2Si nanomaterial-based sustained hydrogen therapy for ALS treatment, establishes a novel gastrointestinal hydrogen delivery strategy, and provides an innovative and clinically translatable paradigm for the design of hydrogen delivery systems against neurodegenerative disorders.
Osteoarthritis (OA) is a multifactorial degenerative joint disorder characterized by intricate interactions among oxidative stress, inflammation, apoptosis, and extracellular matrix (ECM) degradation, ultimately disrupting chondrocyte homeostasis and accelerating cartilage deterioration. Although advanced intra-articular biomaterial systems have improved local therapeutic delivery for OA, the rational integration of a multi-component bioactive core with a multifunctional carrier remains challenging. In this study, a multifunctional nanomedicine, K@BMT@HM, was developed by integrating a supramolecular bioactive core with a functionalized hydrogel microsphere carrier. The K@BMT core, composed of the KRFK peptide, bisdemethoxycurcumin (BDMC), and MnTBAP, exerted multi-dimensional regulatory effects by enhancing antioxidant defense, restoring autophagic flux, and modulating TGF-β-associated signaling, thereby mitigating oxidative stress, inflammation, and apoptosis while favoring ECM anabolic balance in chondrocyte-based assays. However, because TGF-β signaling is highly context- and compartment-dependent, these observations should not be interpreted as evidence that TGF-β activation is uniformly beneficial across the whole joint. Meanwhile, the HM-SCHW carrier, composed of chitosan (CS), sodium alginate (SA), hyaluronic acid (HA), and WYRGRL peptide, provided thermosensitive depot formation, lubrication, cartilage-associated localization/retention, and in vitro sustained/ROS-responsive release, thereby supporting localized delivery potential rather than proving WYRGRL-specific cartilage targeting. Moreover, the laser-responsive thermal behavior of K@BMT@HM provided a controllable local heating modality that may support thermosensitive in situ retention. Remarkably, the integrated K@BMT@HM, which couples the multi-component regulatory capacity of the K@BMT core with the multifunctional delivery advantages of the HM-SCHW carrier, was validated through a series of in vitro and in vivo experiments. Collectively, this work presents a rationally designed nanomedicine that integrates bioactive regulation with functionalized delivery to enhance chondroprotection, supporting further preclinical investigation of sustained and multimodal OA intervention. However, because the laser-assisted thermal component was validated only in a rat small-joint model, these findings cannot be directly extrapolated to human OA joints, where deeper articular cartilage and overlying skin, adipose tissue, synovium, and other tissues may substantially limit optical penetration and thermal delivery. In addition, because systematic single-component, two-component, and component-deletion controls were not performed, the present data should be interpreted as validating the integrated K@BMT@HM system as a whole rather than defining the quantitative contribution or indispensability of BDMC, MnTBAP, KRFK, 808-nm laser activation, the CS/SA hydrogel matrix, HA, or WYRGRL.
Management of systemic lupus erythematosus (SLE) remains challenging: intensive immunosuppression increases infection risk, whereas dose reduction may trigger disease flares. Molecular hydrogen (H2), a selective antioxidant with anti-inflammatory properties, may serve as an adjunct therapy, potentially maintaining disease control while reducing immunosuppressive burden. We present a 43-year-old female with longstanding SLE who experienced recurrent hospitalized infections (pneumonia and complex urinary tract infections) under high-dose immunosuppression in 2022. A subsequent attempt to reduce her medication dosage provoked a significant disease flare in January 2023, with anti-double stranded DNA (anti-dsDNA) levels surging to 890 IU/ml and complement depletion. Oral H2 capsule therapy was initiated as an adjunct. The patient exhibited rapid and robust serologic improvement, allowing for the complete discontinuation of mycophenolic acid within one month. Over an extended follow-up through early 2026, her regimen was successfully de-escalated to a minimized monotherapy of prednisolone 10 mg/day. Her anti-dsDNA levels stabilized within a strictly normal range (<15 IU/ml), with normalized complement levels, no further infections, and profoundly reduced fatigue. Flow-cytometric profiling revealed a coordinated reprogramming of adaptive immunity toward a controlled, non-senescent state, including a homeostatic reset in the B-cell compartment and decreased active-disease-associated T cells. Adjuvant molecular hydrogen therapy stabilized active SLE, enabling substantial reduction of conventional immunosuppressants while maintaining durable clinical and serologic remission. This strategy may represent a promising immunosuppressant-sparing approach and warrants validation in controlled trials.
Extracellular matrix (ECM) turnover and neutrophil protease activity contribute to chronic obstructive pulmonary disease (COPD) pathobiology, but the prognostic value of circulating neoepitopes for acute exacerbations (AECOPD) is uncertain. In a prospective cohort from the CORTICO-COP trial, the biomarkers C5M and C6M (type V/VI collagen degradation), ELP-3 (proteinase 3-generated elastin fragment), and CPa9-HNE (neutrophil elastase-generated calprotectin fragment) were measured in plasma at hospital admission for AECOPD (exacerbation phase; n = 299) and at day-30 follow-up (stable phase; n = 200). The primary endpoint was time to a composite of readmission with AECOPD or all-cause mortality within 12 months; the secondary endpoint was all-cause mortality. Cox models were adjusted for age, sex, pack-years, Charlson Comorbidity Index, and randomization arm. Single-time-point levels were not associated with the composite endpoint or with mortality at exacerbation or at stable phase. In a post-hoc analysis of paired data, a larger decline in CPa9-HNE from admission to day-30 (lowest quartile of change) was associated with a shorter time to the composite endpoint (HR 1.88, 95% CI 1.18-3.01) but not with mortality. This exploratory signal suggests within-patient decline in plasma CPa9-HNE may mark early re-exacerbation risk, but this requires validation in independent cohorts.
In this study, we report a case of decolonisation of a multi-drug-resistant extended spectrum beta-lactamase-producing Escherichia coli, and a vancomycin-resistant Enterococcus faecium after intervention with capsulated faecal microbiota transplantation (FMT). Following eradication, our patient acquired an extended-spectrum beta-lactamase-producing Klebsiella pneumoniae, which was subsequently eliminated after a second round of FMT capsules. Additionally, we report the detection of six distinct carbapenemase-producing organisms in this patient, who was evacuated from the war in Ukraine.
The central problem in heart failure with reduced ejection fraction (HFrEF) is reduced contractility. Existing inotropes are associated with adverse effects. In this exploratory study, we aimed to assess the safety and tolerability of AC01, a novel oral calcium-sensitising inotrope and ghrelin receptor agonist, in patients with HFrEF. In this phase 1b/2a, randomised, double-blind, placebo-controlled study, adults aged 18-80 years with heart failure for at least 6 months and an ejection fraction of 40% or lower were enrolled at 14 sites in the Netherlands, the UK, Sweden, and Italy. All patients had a transvenous implantable cardioverter defibrillator for primary prevention, with back-up pacing to protect against excessive bradycardia. Other eligibility criteria included sinus rhythm or permanent, persistent, or paroxysmal atrial fibrillation or flutter (only allowed in phase 2a), with a mean resting heart rate of 55-90 beats per min. Randomisation used permuted blocks, with block sizes of four for phase 1b and three for phase 2a. In phase 1b, patients were enrolled in four sequential dose cohorts and randomly assigned 3:1 to ascending doses of AC01 (0·1 mg, 0·3 mg, 1·0 mg, or 3·0 mg) or placebo twice daily for 7 days. In phase 2a, patients were randomly assigned 1:1:1 to parallel groups receiving 1·0 mg AC01, 3·0 mg AC01 (1·0 mg AC01 on days 1 and 2 and 3·0 mg thereafter), or placebo orally twice daily for 28 days. Patients, study personnel, outcomes assessors, those analysing the data, and the sponsor were masked to treatment assignment. The primary outcome was safety and tolerability. Safety was monitored by physical examination, vital signs, safety laboratory assessments, and 12-lead electrocardiograms (ECGs) periodically during the treatment period and until the end-of-study visit (day 12 in phase 1b and day 42 in phase 2a), and cardiac rhythm was continuously monitored remotely using a patch device until day 9 in phase 1b and until day 4 in phase 2a. Adverse or unexpected events, signs, or symptoms were recorded. This study is registered with ClinicalTrials.gov, NCT05642507, and has been completed. Between Feb 23, 2023, and Aug 28, 2025, 58 patients (53 [91%] male and five [9%] female patients with a median age of 66·0 years [IQR 60·3-72·0]) were randomly assigned: 32 in phase 1b and 26 in phase 2a. In phase 1b, four cohorts of eight patients were enrolled; in each cohort, six patients were allocated to AC01 and two to placebo, with AC01 dose cohorts of 0·1 mg, 0·3 mg, 1·0 mg, and 3·0 mg. In phase 2a, nine patients were allocated to 1·0 mg AC01, eight to 3·0 mg AC01, and nine to placebo. There were 12 AC01-related adverse events in phase 1b and 18 in phase 2a. There were no AC01-related serious adverse events; one treatment-related serious adverse event of increased high-sensitivity cardiac troponin I concentration occurred in a patient receiving placebo in phase 1b. Mild or moderate treatment-emergent adverse events were reported in 33 (80%) of 41 patients receiving AC01 and 12 (71%) of 17 patients receiving placebo. The most common treatment-emergent adverse events were hypotension, non-sustained ventricular tachycardia, dyspnoea, hyperglycaemia, dizziness or vertigo, and headache. ECG data showed no apparent signs of tachycardia, new-onset tachyarrhythmias, myocardial ischaemia, or morphological or conduction abnormalities. No case of symptomatic hypotension was reported, and there were no apparent effects of AC01 on high-sensitivity cardiac troponin I or NT-proBNP. There were no deaths during the study. In patients with HFrEF, AC01 over 28 days appeared safe and well tolerated, and no major harms were identified in this early-phase study. These findings support further investigations of AC01 in larger studies. AnaCardio.
This study examined whether objective physiological arousal predicts patient-triggered recordings (PTRs) in patients with an implantable loop recorder (ILR), to clarify how normative autonomic activation and clinically meaningful rhythm disturbances relate to symptom-triggered monitoring behavior during long-term surveillance. Data were drawn from 2,266 ILR patients enrolled in the CERTITUDE registry between 2019 and 2025; analyses were restricted to the 878 individuals who used the PTR function at least once. Day-level ILR data from the first 12 months following implantation were analyzed. Daily physical activity percent per day (PA), weekly variability in PA, and counts of device-detected atrial fibrillation, bradycardia, and asystole were modeled as predictors of daily PTR counts using within-person repeated-measures correlations and linear mixed-effects models. Subgroup analyses were conducted by primary clinical indication. Daily PA showed near-zero within-person associations with PTR behavior (overall r = - .018), and mixed-effects models yielded very small coefficients. Weekly PA variability was not associated with PTR activation. Device-detected arrhythmic events accounted for only marginal additional variance in PTR counts, and asystole was not associated with PTR use. Patterns were consistent across ILR indications. Overall, objective physiological arousal explained little of the observed variation in PTR behavior. PTR behavior during long-term ILR monitoring appears to be shaped largely by interpretive and decisional processes, rather than by direct detection of physiological events alone. Conceptualizing PTRs as behavioral responses to ambiguity in bodily sensations highlights the importance of patient education, contextualized physiological feedback, and attention to symptom appraisal in the clinical management of ILR patients.
Hidradenitis suppurativa (HS) is a debilitating skin disease marked by recurrent abscesses and chronic inflammation. Immune checkpoint inhibitors (ICIs) are widely used oncologic treatments that can provoke immune-mediated effects. The ICI potential to precipitate HS onset or influence HS disease activity remains uncharacterized. We aim to characterize the timing, clinical features, severity, and outcomes of HS in this context. Scoping review according to PRISMA guidelines was conducted. Studies were identified through PubMed and MEDLINE searches and were eligible if they reported at least 1 case of HS onset or worsening in the setting of ICI therapy. Five publications comprising 13 patients were included. Pembrolizumab was the most frequently used ICI (46.2%). Eight individuals (61.5%) had pre-existing HS, of whom 3 (37.5%) experienced flares during therapy. Five patients (38.5%) developed new-onset HS after ICI initiation, within 2-4 months. Treatment approaches varied and included topical and systemic therapies for HS. Four patients (30.8%) experienced complete resolution of HS lesions following ICI discontinuation. ICI therapy may precipitate new-onset HS or exacerbate pre-existing disease in a subset of patients. Increased clinical vigilance and early dermatologic involvement may support timely diagnosis, optimize management, and preserve continuity of oncologic care. Hidradenitis suppurativa (HS) is an inflammatory skin condition that has overlap with other conditions such as cancer. It is not well described how a type of cancer treatment, called immune checkpoint inhibitors (ICI), can affect HS. This scoping review evaluated case reports, totaling 13 patients. Less than half developed new HS, and of the patients with existing HS, only half experienced a flare. More research is needed to further understand the incidence, clinical course, and management of HS patients taking ICI treatment.
Small, dense low-density lipoprotein (sdLDL) particles are considered a highly atherogenic subfraction of LDL. Automated biochemical measurement of sdLDL cholesterol (sdLDL-C) has good fidelity to gold-standard measurements. We evaluated relationships of sdLDL-C and LDL-C to risk of major adverse cardiovascular events (MACE) and treatment benefit of the PCSK9-directed monoclonal antibody alirocumab in patients with recent acute coronary syndrome (ACS) and elevated atherogenic lipoproteins despite optimized statin treatment. Analyses comprised 11,837 participants in the ODYSSEY OUTCOMES trial randomized to receive alirocumab or placebo. sdLDL-C was measured using the Denka method; baseline LDL-C was calculated with the Friedewald formula. In the placebo group (n = 5920), cubic splines depicted relationships of sdLDL-C, LDL-C, and their ratio to risk of MACE (cardiovascular death, non-fatal myocardial infarction, ischemic stroke, hospitalization for unstable angina, and ischemia-driven coronary revascularization). Treatment hazard ratio (HR) was calculated across sdLDL-C and LDL-C ranges. Over 2.8 years median follow-up, risk of MACE in the placebo group increased with higher baseline sdLDL-C or LDL-C with nearly superimposable splines and without variation according to sdLDL-C/LDL-C. Findings were similar in patients with greater or lesser degrees of insulin resistance. Alirocumab reduced risk of MACE (HR 0.87, 95% CI 0.79, 0.95). Treatment HR did not vary significantly across the range of LDL-C or sdLDL-C. In patients with recent ACS on optimized statin treatment, sdLDL-C and LDL-C similarly predict risk of MACE and benefit of alirocumab treatment. Measurement of sdLDL-C does not appear to provide additional prognostic or predictive information in this population.