Search Results (585)

Introduction: The combination of ceftazidime−avibactam (CAZ-AVI) with aztreonam (ATM) may be an option for the treatment of infections due to metallo-β-lactamases (MBLs) producing bacteria, as recommended by current guidelines. MBLs protect the pathogen from any available β-lactam/β-lactamase inhibitor (BL/BLI). Moreover, in vitro and clinical data suggest that double carbapenem therapy (DCT) may be an option for such infections. Materials and Methods: This retrospective study was conducted in two mixed intensive care units (ICUs) at the University Hospital of Larissa, Thessaly, Greece, and the General Hospital of Larissa, Thessaly, Greece, during a three-year period (2022−2024). Mechanically ventilated patients with bloodstream infection (BSI) caused by K. pneumoniae resistant to all BL/BLI combinations were studied. Patients were divided into three groups: in the first, patients were treated with CAZ-AVI + ATM; in the second, with DCT; and in the third, with antibiotics other than BL/BLIs that presented in vitro susceptibility. The primary outcome of the study was the change in Sequential Organ Failure Assessment (SOFA) score between the onset of infection and the fourth day of antibiotic treatment. Secondary outcomes were SOFA score evolution during the treatment period, total duration of mechanical ventilation (MV), ICU length of stay (LOS), and ICU mortality. Results: A total of 95 patients were recruited. Among them, 23 patients received CAZ-AVI + AZT, 22 received DCT, and 50 patients received another antibiotic regimen which was in vitro active against the pathogen. The baseline characteristics were similar. The mean (SE) overall age was 63.2 (1.3) years. Mean (SE) Acute Physiology and Chronic Health Evaluation II (APACHE II) and SOFA scores were 16.3 (0.6) and 7.6 (0.3), respectively. The Charlson Index was similar between groups. The control group presented a statistically lower SOFA score on day 4 compared to the other two groups [mean (SE) 8.9 (1) vs. 7.4 (0.9) vs. 6.4 (0.5) for CAZ-AVI + ATM, DCT and control group, respectively (p = 0.045)]. The duration of mechanical ventilation, ICU LOS, and mortality were similar between the groups (p > 0.05). Comparison between survivors and non-survivors revealed that survivors had a lower SOFA score on the day of BSI, higher PaO₂/FiO₂ ratio, higher platelet counts, and lower lactate levels (p < 0.05). Septic shock was more frequent among non-survivors (60.3%) in comparison to survivors (27%) (p = 0.0015). Independent factors for mortality were PaO₂/FiO₂ ratio and lactate levels (p < 0.05). None of the antibiotic regimens received by the patients was independently associated with survival. Conclusions: Treatment with CAZ-AVI + ATM or DCT may offer similar clinical outcomes for patients suffering from BSI caused by K. pneumoniae strains resistant to all available BL/BLIs. However, larger studies are required to confirm the findings. Full article

Background: Immune checkpoint inhibitor therapy in patients with lung cancer and metastatic melanoma is associated with exacerbation of autoimmune-related diseases. The efficacy of treatment targeting the programmed cell death receptor-1 (PD-1) checkpoint relies upon a feedback loop between interferon gamma (IFN-γ) and the interleukin-12 isoform, IL-12p40. Paradoxically, both cytokines and the anti-PD-1 antibody worsen psoriasis. We previously reported an immunomodulating peptide, designated IK14004, that inhibits progression of Lewis lung cancer in mice yet uncouples IFN-γ from IL-12p40 production in human immune cells. Methods: Immune cells obtained from healthy donors were exposed to IK14004 in vitro to further characterise the signalling pathways affected by this peptide. Using C57BL/6 immunocompetent mice, the effect of IK14004 was tested in models of lung melanoma and psoriatic skin. Results: Differential effects of IK14004 on the expression of IFN-α/β, the interleukin-15 (IL-15) receptor and signal transducers and activators of transcription were consistent with immune responses relevant to both cancer surveillance and immune tolerance. Moreover, both melanoma and psoriasis were inhibited by the peptide. Conclusions: Taken together, these findings suggest mechanisms underlying immune homeostasis that could be exploited in the setting of cancer and autoimmune pathologies. Peptide administered together with checkpoint blockers in relevant models of autoimmunity and cancer may offer an opportunity to gain further insight into how immune tolerance can be retained in patients receiving cancer immunotherapy. Full article

The ability to quantify equine kinematics is essential for clinical evaluation, research, and performance feedback. However, current methods are challenging to implement. This study presents a motion capture methodology for horses, where three-dimensional, full-body kinematics are calculated without instrumentation on the animal, offering a more scalable and labor-efficient approach when compared with traditional techniques. Kinematic trajectories are calculated from multi-camera video data. First, a neural network identifies skeletal landmarks (markers) in each camera view and the 3D location of each marker is triangulated. An equine biomechanics model is scaled to match the subject’s shape, using segment lengths defined by markers. Finally, inverse kinematics (IK) produces full kinematic trajectories. We test this methodology on a horse at three gaits. Multiple neural networks (NNs), trained on different equine datasets, were evaluated. All networks predicted over 78% of the markers within 25% of the length of the radius bone on test data. Root-mean-square-error (RMSE) between joint angles predicted via IK using ground truth marker-based motion capture data and network-predicted data was less than 10 degrees for 25 to 32 of 35 degrees of freedom, depending on the gait and data used for network training. NNs trained over a larger variety of data improved joint angle RMSE and curve similarity. Marker prediction error, the average distance between ground truth and predicted marker locations, and IK marker error, the distance between experimental and model markers, were used to assess network, scaling, and registration errors. The results demonstrate the potential of markerless motion capture for full-body equine kinematic analysis. Full article

Background: Gait kinematics address the analysis of joint angles and segment movements during walking. Although there is work in the literature to solve the problems of forward (FK) and inverse kinematics (IK), there are still problems related to the accuracy of the estimation of Cartesian and joint variables, singularities, and modeling complexity on gait analysis approaches. Objective: In this work, we propose a framework for two-dimensional gait analysis addressing the singularities in the estimation of the joint variables using quaternion-based kinematic modeling. Methods: To solve the forward and inverse kinematics problems we use the dual quaternions’ composition and Damped Least Square (DLS) Jacobian method, respectively. We assess the performance of the proposed methods with three gait patterns including normal, toe-walking, and heel-walking using the RMSE value in both Cartesian and joint spaces. Results: The main results demonstrate that the forward and inverse kinematics methods are capable of calculating the posture and the joint angles of the three-DoF kinematic chain representing a lower limb. Conclusions: This framework could be extended for modeling the full or partial human body as a kinematic chain with more degrees of freedom and multiple end-effectors. Finally, these methods are useful for both diagnostic disease and performance evaluation in clinical gait analysis environments. Full article

In this work, we introduce IK-AUG, a unified algorithmic framework for kinematics-driven data augmentation tailored to sign language recognition (SLR). Departing from traditional augmentation techniques that operate at the pixel or feature level, our method integrates inverse kinematics (IK) and virtual simulation to synthesize anatomically valid gesture sequences within a structured 3D environment. The proposed system begins with sparse 3D keypoints extracted via a pose estimator and projects them into a virtual coordinate space. A differentiable IK solver based on forward-and-backward constrained optimization is then employed to reconstruct biomechanically plausible joint trajectories. To emulate natural signer variability and enhance data richness, we define a set of parametric perturbation operators spanning spatial displacement, depth modulation, and solver sensitivity control. These operators are embedded into a generative loop that transforms each original gesture sample into a diverse sequence cluster, forming a high-fidelity augmentation corpus. We benchmark our method across five deep sequence models (CNN3D, TCN, Transformer, Informer, and Sparse Transformer) and observe consistent improvements in accuracy and convergence. Notably, Informer achieves 94.1% validation accuracy with IK-AUG enhanced training, underscoring the framework’s efficacy. These results suggest that algorithmic augmentation via kinematic modeling offers a scalable, annotation free pathway for improving SLR systems and lays the foundation for future integration with multi-sensor inputs in hybrid recognition pipelines. Full article

Axis definition plays a key role in the establishment of animal body plans, both in normal development and regeneration. The cnidarian Hydra can re-establish its simple body plan when regenerating from a random cell aggregate or a sufficiently small tissue fragment. At the beginning of regeneration, a hollow cellular spheroid forms, which then undergoes symmetry breaking and de novo body axis definition. In the past, we have published related work in a physics journal, which is difficult to read for scientists from other disciplines. Here, we review our work for readers not so familiar with this type of approach at a level that requires very little knowledge in mathematics. At the same time, we present a few aspects of Hydra biology that we believe to be linked to our work. These biological aspects may be of interest to physicists or members of related disciplines to better understand our approach. The proposed theoretical model is based on fluctuations of gene expression that are triggered by mechanical signaling, leading to increasingly large groups of cells acting in sync. With a single free parameter, the model quantitatively reproduces the experimentally observed expression pattern of the gene ks1, a marker for ‘head forming potential’. We observed that Hydra positions its axis as a function of a weak temperature gradient, but in a non-intuitive way. Supposing that a large fluctuation including ks1 expression is locked to define the head position, the model reproduces this behavior as well—without further changes. We explain why we believe that the proposed fluctuation-based symmetry breaking process agrees well with recent experimental findings where actin filament organization or anisotropic mechanical stimulation act as axis-positioning events. The model suggests that the Hydra spheroid exhibits huge sensitivity to external perturbations that will eventually position the axis. Full article

Synthetic flavors from standardized processes have recently emerged as a promising and sustainable alternative to traditional feed attractants. In this study, two attractive (F25, cheese; F35, caramel) and one repulsive (F32-, coconut) synthetic flavors were individually added (1% w/w) to a commercial diet for European seabass (Dicentrarchus labrax) and tested over a 90-day feeding trial (30 fish per tank, in triplicate; initial weight 72.48 ± 8.04 g) to assess their impact on fish growth performance, welfare, and the modulation of brain appetite and monoaminergic pathways. None of the tested flavors negatively affected overall fish health. The F35 flavor enhanced feed intake (90.1 ± 5.6%) and growth (SGR 2.2 ± 0.2%) and positively influenced appetite-related and monoaminergic signals, thus being more effective than the F25 one (80.4 ± 3.2 and 1.6 ± 0.1%, respectively). A weekly feeding rotation between F35 and F25 (ROT group) resulted in suboptimal outcomes compared to F35 administration alone. The F32- flavor was not clearly perceived as strongly aversive by seabass and did not impair zootechnical performance. These findings highlight the potential of attractive synthetic flavors to improve diet palatability in a carnivorous species of commercial value, offering novel insights for more sustainable and cost-effective aquaculture feeding strategies. Full article

Long- or post-COVID-19 syndrome, which is also designated by WHO as Post COVID-19 Condition (PCC), is characterized by the persistent symptoms that remain after recovery from SARS-CoV-2 infection. A worldwide consortium of Long COVID-19 Host Genetics Initiative (Long COVID-19 HGI) identified an SNP rs9367106 (G>C; chr6:41,515,652, GRCh38, p = 1.76 × 10⁻¹⁰, OR = 1.63, 95% CI: 1.40–1.89) that is associated with PCC. Unraveling the functional significance of this SNP is of prime importance to understanding the development of the PCC phenotypes and their therapy. Here, in Silico, I explored how the risk allele of this SNP alters the functional mechanisms and molecular pathways leading to the development of PCC phenotypes. Bioinformatic methods include physical interactions using HI-C and Chia-PET analysis, Transcription Factors (TFs) binding ability, RNA structure modeling, epigenetic, and pathway analysis. This SNP resides within two long RNA genes, LINC01276 and FOXP4-AS1, and is located at ~31 kb upstream of a transcription factor FOXP4. This DNA region, including this SNP, physically interacts with FOXP4-AS1 and FOXP4, implying that this regulatory SNP could alter the normal cellular function of FOXP4-AS1 and FOXP4. Furthermore, rs9367106 is in eQTL with the FOXP4 gene in lung tissue. rs9367106 carrying DNA sequences act as distant enhancers and bind with several transcription factors (TFs) including YY1, PPAR-α, IK-1, GR-α, and AP2αA. The G>C transition extensively modifies the RNA structure that may affect the TF bindings and enhancer functions to alter the interactions and functions of these RNA molecules. This SNP also includes an ALU/SINE sequence and alteration of which by the G>C transition may prevent IFIH1/MDA5 activation, leading to suppression of host innate immune responses. LINC01276 targets the MED20 gene that expresses mostly in brain tissues, associated with sleep disorders and basal ganglia abnormalities similar to some of the symptoms of PCC phenotypes. Taken together, G>C transition of rs9367601 may likely alter the function of all three genes to explain the molecular basis of developing the long-term symptomatic abnormalities in the lungs and brain observed after COVID-19 recovery. Full article

Fibrosis represents a pivotal pathological process in numerous diseases, characterized by excessive deposition of extracellular matrix (ECM) that disrupts normal tissue architecture and function. In the heart, cardiac fibrosis significantly impairs both structural integrity and functional capacity, contributing to the progression of heart failure. Central to this process are cardiac fibroblasts (CFs), which, upon activation, differentiate into contractile myofibroblasts, driving pathological ECM accumulation. Transforming growth factor-beta (TGFβ) is a well-established regulator of fibroblast activation; however, the precise molecular mechanisms, particularly the involvement of ion channels, remain poorly understood. Emerging evidence highlights the regulatory role of ion channels, including calcium-activated potassium (K_Ca) channels, in fibroblast activation. This study elucidates the role of ion channels and investigates the mechanism by which Yoda1, an agonist of the mechanosensitive ion channel Piezo1, modulates TGFβ-induced fibroblast activation. Using NIH/3T3 fibroblasts, we demonstrated that TGFβ-induced activation is regulated by tetraethylammonium (TEA)-sensitive potassium channels, but not by specific K⁺ channel subtypes such as BK, SK, or IK channels. Intriguingly, Yoda1 was found to inhibit TGFβ-induced fibroblast activation through a Piezo1-independent mechanism. Transcriptomic analysis revealed that Yoda1 modulates fibroblast activation by altering gene expression pathways associated with fibrotic processes. Bromodomain-containing protein 4 (BRD4) was identified as a critical mediator of Yoda1’s effects, as pharmacological inhibition of BRD4 with JQ1 or ZL0454 suppressed TGFβ-induced expression of the fibroblast activation marker Periostin (Postn). Conversely, BRD4 overexpression attenuated the inhibitory effects of Yoda1 in both mouse and rat CFs. These results provide novel insights into the pharmacological modulation of TGFβ-induced cardiac fibroblast activation and highlight promising therapeutic targets for the treatment of fibrosis-related cardiac pathologies. Full article

Klebsiella pneumoniae is a major public health concern due to its role in Gram-negative bacteremia, which leads to high mortality and increased healthcare costs. This study characterizes phenotypic and genomic features of K. pneumoniae isolates from clinical samples in Karachi, Pakistan. Among 507 isolates, 213 (42%) were carbapenem-resistant based on disk diffusion and MIC testing. Urine (29.7%) and blood (28.3%) were the most common sources, with infections predominantly affecting males (64.7%) and individuals aged 50–70 years. Colistin was the only antibiotic showing consistent activity against these isolates. The whole-genome sequencing of 24 carbapenem-resistant K. pneumoniae (CR-KP) isolates revealed bla_NDM-5 (45.8%) as the dominant carbapenemase gene, followed by bla_NDM-1 (12.5%) and bla_OXA-232 (54.2%). Other detected bla_OXA variants included bla_OXA-1, bla_OXA-4, bla_OXA-10, and bla_OXA-18. The predominant beta-lactamase gene was bla_CTX-M-15 (91.6%), followed by bla_CTX-M-163, bla_CTX-M-186, and bla_CTX-M-194. Sequence types ST147, ST231, ST29, and ST11 were associated with resistance. Plasmid profiling revealed IncR (61.5%), IncL (15.4%), and IncC (7.7%) as common plasmid types. Importantly, resistance was driven not only by acquired genes but also by chromosomal mutations. Porin mutations in OmpK36 and OmpK37 (e.g., P170M, I128M, N230G, A217S) reduced drug influx, while acrR and ramR mutations (e.g., P161R, G164A, P157*) led to efflux pump overexpression, enhancing resistance to fluoroquinolones and tigecycline. These findings highlight a complex resistance landscape driven by diverse carbapenemases and ESBLs, underlining the urgent need for robust antimicrobial stewardship and surveillance strategies. Full article

This retrospective cohort study evaluated characteristics, treatment patterns, and clinical outcomes in adults with locally advanced/metastatic urothelial carcinoma (la/mUC) receiving first-line (1L) systemic treatment with or without avelumab 1L maintenance (1LM) between January 2020 and July 2023. The index date was the first date with a claim for 1L systemic therapy after a la/mUC diagnosis. Patients with continuous health plan enrollment for ≥6 months before and ≥1 month after the index date were identified from Carelon Research’s Healthcare Integrated Research Database. Of 2820 patients receiving 1L treatment, 37.0% received platinum-based chemotherapy (PBC); 39.0%, immuno-oncology (IO) monotherapy; and 24.0%, other therapies. Renal disease and other comorbidities influenced 1L regimen choice. Healthcare resource utilization (HCRU) and costs were reported for patients receiving second-line (2L) treatment. HCRU was high in 32.8% of patients (926 of 2820) who received 2L treatment. Median all-cause direct medical costs per patient per month were USD 15,859, USD 19,781, USD 11,346, and USD 9516 for 1L PBC, 1L PBC + avelumab 1LM, 1L IO monotherapy, and 1L other therapies, respectively. Most direct healthcare costs were attributed to all-cause outpatient visits. Full article

Background: The implementation of artificial intelligence (AI) has become a pivotal interdisciplinary challenge, creating new opportunities for sharing information, driving innovation, and transforming societal interactions with technology. While AI offers numerous benefits, its rapid evolution raises critical concerns about its impact on inclusion, diversity, equity, accessibility, and safety (IDEAS). Method: This pilot study aimed to explore these issues and identify ways to embed the IDEAS principles into AI design. A qualitative study was conducted with industrial and academic experts in the field. Semi-structured interviews gathered insights into the opportunities, challenges, and future implications of AI from diverse professional and cultural perspectives. Result: Findings highlight uncertainties in AI’s trajectory and its profound cross-sector influence. Key issues emerged, including bias, data privacy, transparency, and accessibility. Participants stressed the need for greater awareness and structured dialogue to integrate the IDEAS principles throughout the AI lifecycle. Conclusion: This study underscores the urgency of addressing AI’s ethical and societal impacts. Embedding the IDEAS principles into its development can help mitigate risks and foster more inclusive, equitable, and accessible technologies. Full article

This paper explores the application of Deep Neural Networks (DNNs) to solve the Inverse Kinematics (IK) problem in robotic manipulators. The IK problem, crucial for ensuring precision in robotic movements, involves determining joint configurations for a manipulator to reach a desired position or orientation. Traditional methods, such as analytical and numerical approaches, have limitations, especially for redundant manipulators, or involve high computational costs. Recent advances in machine learning, particularly with DNNs, have shown promising results and seem fit for addressing these challenges. This study investigates several DNN architectures, namely Feed-Forward Multilayer Perceptrons (MLPs), Convolutional Neural Networks (CNNs), and Recurrent Neural Networks (RNNs), for solving the IK problem, using the TIAGo robotic arm with seven Degrees of Freedom (DOFs). Different training datasets, normalization techniques, and orientation representations are tested, and custom metrics are introduced to evaluate position and orientation errors. The performance of these models is compared, with a focus on curriculum learning to optimize training. The results demonstrate the potential of DNNs to efficiently solve the IK problem while avoiding issues such as singularities, competing with traditional methods in precision and speed. Full article

The volatile organic compounds (VOCs) produced by K. cowanii Ch1 play a significant role in the inhibition of the mycelial growth of phytopathogen strains. As a continuation of our previous studies, we aim to elucidate the mechanisms of the responses of K. cowanii Ch1 against S. rolfsii during a colonization competence interaction in the presence and absence of a mixture of bacterial VOCs under in vitro conditions. The results of this study showed that, in the absence of bacterial VOCs, K. cowanii Ch1 cannot compete against S. rolfsii, and the RNA-Seq analysis revealed the differential expression of genes related to the oxidative stress response in K. cowanii Ch1 for survival. However, in the presence of bacterial VOCs, an interesting phenotypical response was observed in K. cowanii Ch1, resulting in the mycelial growth inhibition of S. rolfsii. The upregulated genes were related to the siderophore-mediated iron transport system, zinc ion transport system, antibiotic biosynthesis monooxygenase, carbohydrate metabolism, polyketide synthase modules, and related proteins, and katG was probably related to the phenotype resulting in the formation of gas bubbles by K. cowanii. In addition, the VOC profile analyzed at 36 h for bacterial growth revealed a cocktail with an ability to increase the competence of K. cowanii Ch1 against S. rolfsii in vitro and in vivo. This study provides evidence regarding the key role that VOCs play during the colonization competition involving K. cowanii Ch1, the comprehension of which may enable the development of new biocontrol strategies. Full article

This study evaluated the histopathological impact of three commonly used pesticides—pirimiphos-methyl, propamocarb hydrochloride, and 2,4-dichlorophenoxyacetic acid (2,4-D)—on the kidneys of common carp (Cyprinus carpio Linnaeus, 1758) after 96-h acute exposure. The histopathological analysis demonstrated that all three tested pesticides induced structural changes. The histopathological changes were assessed using a semi-quantitative scoring system and categorised into circulatory, degenerative, proliferative, and inflammatory alterations. While circulatory alterations were absent in all treatments, clear and statistically significant degenerative, proliferative, and inflammatory responses were recorded, which escalated with increasing pesticide concentrations. Additionally, various statistical analyses were conducted to evaluate the lesions in kidney structure and function. Before the statistical analysis, normality and variance homogeneity were assessed using the Shapiro–Wilk and Levene’s tests, respectively. Due to non-normal data distribution, non-parametric methods were applied. Hence, the non-parametric statistical methods showed distinct group-level differences in the kidney damage indices. The Kruskal–Wallis test revealed significant differences across treatments (p < 0.001), and Mann–Whitney U tests identified specific pairwise differences. The degenerative and proliferative lesions were most prominent in fish exposed to 2,4-D at 100 µg/L (IK = 34), followed by pirimiphos-methyl and propamocarb hydrochloride. Inflammatory changes were mainly observed in the pirimiphos-methyl groups. The histopathological lesions were concentration-dependent, with 2,4-D causing irreversible renal damage at higher concentrations. These findings highlight the nephrotoxic risks posed by common pesticides and validate that the use of histopathological indices, combined with robust non-parametric testing, provides a reliable approach to evaluating organ-specific pesticide toxicity. These biomarkers offer sensitive early warning indicators of environmental risk, reinforcing the suitability of common carp as a model species for ecotoxicological assessment. Full article