Paphos General Hospital

The selection of appropriate activation functions has become an important research domain around neural networks. The aim of the present article is to investigate the properties of trainable rectified linear unit (ReLU) transfer function from performance of neural network point of view. We focus on the role of trainable parameters for ReLU activation function to achieve high neural network performance. We also give a comparative analysis for MLP-Mixer using trainable ReLU activation function and GELU. Simulation results are presented that show the improved accuracy capability.

This paper presents a cross-layer intrusion detection framework leveraging explainable artificial intelligence (XAI) and interpretability methods to enhance transparency and robustness in attack detection within the Internet of Medical Things (IoMT) domain. By addressing the dual challenges of compromised data integrity, which span both biosensor and network-layer data, this study combines advanced techniques to enhance interpretability, accuracy, and trust. Unlike conventional flow-based intrusion detection systems that primarily rely on transport-layer statistics, the proposed framework operates directly on raw packet-level features and application-layer semantics, including MQTT message types, payload entropy, and topic structures. The key contributions of this research include the application of K-Means clustering combined with the principal component analysis (PCA) algorthim for initial categorization of attack types, the use of SHapley Additive exPlanations (SHAP) for feature prioritization to identify the most influential factors in model predictions, and the employment of Partial Dependence Plots (PDP) and Accumulated Local Effects (ALE) to elucidate feature interactions across layers. These methods enhance the system’s interpretability, making data-driven decisions more accessible to nontechnical stakeholders. Evaluation on a realistic healthcare IoMT testbed demonstrates significant improvements in detection accuracy and decision-making transparency. Furthermore, the proposed approach highlights the effectiveness of explainable and cross-layer intrusion detection for secure and trustworthy medical IoT environments that are tailored for cybersecurity analysts and healthcare stakeholders.

Human echinococcosis (hydatidosis or hydatid) disease is a worldwide neglected zoonotic larval infection typically caused by cestodes of the Echinococcus genus. It affects 1 million people worldwide, predominantly reported in Central Asia, the Middle East, and South America. In this paper, we report a patient who underwent a successful laparoscopic partial pericystectomy and omentoplasty with simultaneous cholecystectomy in the treatment of cystic echinococcosis and cholelithiasis, respectively. There are many challenges to treating complicated hepatic hydatid cysts. It is crucial for surgeons to have knowledge of the range of possibilities of each surgical modality and its expanding advancements that can reduce complication risks and increase a patient’s quality of life. The art of sharing techniques and management possibilities between professionals in this field provides a bridge in further crafting the best-tailored treatment plan for patients. This report illustrates the successful usage of laparoscopy in the management of a section IV hydatid cyst with simultaneous cholecystectomy. This case aims to expand the knowledge and prospects of laparoscopic surgery in cystic echinococcosis.

Diabetes mellitus (DM) is a multifaceted disorder with a pandemic spread and a remarkable burden of cardiovascular mortality and morbidity. Diabetic cardiomyopathy (DBCM) has been increasingly recognized as the development of cardiac dysfunction, which is accompanied by heart failure (HF) symptoms in the absence of obvious reasons like ischemic heart disease, hypertension, or valvulopathies. Several pathophysiological mechanisms have been proposed, including metabolic disorders (e.g., glycation products), oxidative stress, low-grade inflammation, mitochondrial dysfunction, etc., which should guide the development of new therapeutic strategies. Up to now, HF treatment has not differed between patients with and without diabetes, which limits the expected benefits despite the high cardiovascular risk in the former group. However, DBCM patients may require different management, which prioritize anti-diabetic medications or testing other novel therapies. This review aims to appraise the challenges and prospectives of the individualized pharmaceutical therapy for DBCM.

BackgroundPVR (CD155) and CD112 are two ligands from Nectin/Nectin-like family which are frequently expressed on different types of tumor cells. PVR binds to inhibitory receptors TIGIT and CD96 triggering a direct inhibitory signal in T and NK-cells and binds to co-stimulatory receptor DNAM1 (CD226) causing its downregulation. CD112 binds to inhibitory receptor PVRIG expressed on T and NK-cells and to DNAM1 stimulating T and NK-cells. Late-stage clinical trials of anti-TIGIT monoclonal antibodies (mAbs) showed controversial efficacy results.1 2 The aim the work was to compare how inhibition of TIGIT, PVRIG, PVR or their combinations affects engagement of TIGIT, CD96, PVRIG and DNAM1 using mathematical modeling.MethodsWe developed a mechanistic model describing surface PVR, CD112 on cancer cell and TIGIT, CD96, DNAM1, PVRIG on CD8 T-cell and interaction of these ligands and receptors in immunological synapse (IS) between these cells in the tumor. In vitro data and data on expression of described ligands and receptors in blood and tumor were used to identify parameters. Validation of the model was done against data on downmodulation of DNAM1 and TIGIT on CD8 T-cells in the tumor in comparison to the blood. Total DNAM1 on the surface of CD8 T-cell in the tumor and engagement of TIGIT, CD96, PVRIG and DNAM1 in IS (i.e., numbers of PVR:TIGIT, PVR:CD96, CD112:PVRIG, PVR:DNAM1 and CD112:DNAM1 complexes) were simulated under 100% inhibition of TIGIT, PVR, PVRIG, TIGIT and PVRIG, or PVR and PVRIG.ResultsTIGIT blockade didn’t increase total DNAM1 and bound DNAM1 in IS. Inhibition of PVRIG resulted in increase of bound DNAM1 (in ~1.3 times), but not total DNAM1 (figure 1). Combination of TIGIT and PVRIG blockade didn’t increase engaged DNAM1 above levels observed in anti-PVRIG monotherapy. Inhibition of PVR resulted in strong increase of total DNAM1 and moderate increase of bound DNAM1 (in ~1.3 times) in addition to disruption of TIGIT and CD96 engagements. Combination of PVR and PVRIG blockade resulted in the strongest increase of bound DNAM1 (in ~ 2 times) in addition to disruption of TIGIT, CD96 and PVRIG engagements.ConclusionsThe failure to enhance DNAM1 engagement during TIGIT inhibition could explain the inability of tiragolumab (anti-TIGIT mAb) to provide additional benefit over atezolizumab in lung cancer.2 Targeting PVR alone or in combination with PVRIG is predicted to be better strategy than targeting TIGIT or TIGIT in combination with PVRIG.ReferencesCho BC, Abreu DR, Hussein M. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study. Lancet Oncol 2022 Jun;23(6):781–792.Rudin CM, Liu SV, Soo RA. SKYSCRAPER-02: tiragolumab in combination with atezolizumab plus chemotherapy in untreated extensive-stage small-cell lung cancer. J Clin Oncol 2024 Jan 20;42(3):324–335. 536 Figure 1Model predictions

BackgroundCetuximab is a recombinant human/mouse chimeric epidermal growth factor receptor (EGFR) monoclonal antibody. Cetuximab mechanisms of action is based on disruption of EGFR signaling pathways as dominant mechanism and ADCC effect as a secondary one. The aims of this study were (1) to develop a model describing Cetuximab mechanism of action and effect on head and neck cancer cell lines observed in vitro with a purpose to integrate them in quantitative systems pharmacology (QSP) model of HNSCC and (2) to apply the in vitro model to study contributions of EGFR signaling disruption vs ADCC of Cetuximab for different E:T ratios.MethodsA model describing Cetuximab mechanism of action includesTumor and NK cellsTumor cell proliferation and processes describing NK dependent and independent deathImmunological synapse formed by Tumor and NK cellBinding of EGF to EGFR located at the surface of Tumor cells and disruption of the signaling complex with CetuximabFormation of trimer between EGFR located on tumor cell, cetuximab and Fcg3A receptor on NK cellsDirect effect of cetuximab on tumor cell proliferation via decrease in signaling complexes EGF-EGFRADCC effect of cetuximab on Tumor cell death via stimulation of NK-mediated cytotoxicity with trimer EGFR-Cetuximab- FcgR3AThe model was calibrated against following datasets:EGF effect on cell culture growth: UM-SCC-31Time course of cell culture growth treated with Cetuximab, NK, Cetuximab +NK for 48 hours: SCC22b2Dependence of ADCC on Cetuximab dose treated with Cetuximab +NK for 4 hours: Ho-1-u-13ResultsValidation of the model was performed to confirm its predictive power. Datasets describing survival, cytotoxicity and ADCC as functions of E:T ratio and EGFR expression level were successfully reproduced (see example in figure 1). The model was applied to analyze contribution of signaling/direct effect of Cetuximab and ADCC for different E:T ratios. We have found that contribution of ADCC is observed starting from E:T = 1:100. Model predicts that ADCC effect contribution is comparable with that of signaling/direct effect of cetuximab in following range E:T = 1:2 – 1:1. Starting from E:T = 1:1 ADCC contribution exceeds that of signaling/direct effect.ConclusionsThe developed model can adequately describe the effects of Cetuximab observed in in vitro experiments. The model was applied to estimate contribution of ADCC and direct effect of Cetuximab at various E:T ratios and EGFR expression levels.ReferencesMakarova G, Bette M, Schmidt A, Jacob R, Cai C, Rodepeter F, Betz T, Sitterberg J, Bakowsky U, Moll R, Neff A, Sesterhenn A, Teymoortash A, Ocker M, Werner JA, Mandic R. Epidermal growth factor-induced modulation of cytokeratin expression levels influences the morphological phenotype of head and neck squamous cell carcinoma cells. Cell Tissue Res. 2013;351(1):59–72.Baysal H, De Pauw I, Zaryouh H, De Waele J, Peeters M, Pauwels P, Vermorken JB, Smits E, Lardon F, Jacobs J, Wouters A. Cetuximab-induced natural killer cell cytotoxicity in head and neck squamous cell carcinoma cell lines: investigation of the role of cetuximab sensitivity and HPV status. Br J Cancer. 2020;123(5):752–761.Nakamura H, Tamaki S, Yagyuu T, Yamakawa N, Hatake K, Kirita T. Relationship Between EGFR Expression in Oral Cancer Cell Lines and Cetuximab Antibody-dependent Cell-mediated Cytotoxicity. Anticancer Res. 2019;39(3):1275–1282. 1280 Figure 1Correspondence between experimental data (dots) [3] and simulations (lines) describing cytotoxicity of NK cells with (magenta) and without (blue) 10 ug/ml Cetuximab. Target cells (Ho-1-u-1 cell line) were incubated with NK and Cetuximab for 4 hours and Cytotoxicity was plotted as function of effector:target ratio

Direct oral anticoagulants (DOACs) have been approved, for over a decade, by both European and American medicine agencies, for treatment and prevention of several cardiovascular conditions. Since then, an increasing amount of data has been added to the medical literature day by day, resulting in a dichotomy in selection of the appropriate agent, dosage, and duration of treatment for special populations with multiple comorbidities. Considering these issues, we have prepared a comprehensive review for the clinical practitioner, to optimize the DOAC utilization in clinical practice. A thorough literature search and review was conducted, concerning mainly the last decade. Our review focused on the current guidelines and the most recently published studies in PubMed, Science Direct Scopus, and Google Scholar to date. The purpose of this study is to provide guidance for healthcare professionals for making proper decisions when confronted with clinical challenges. Nevertheless, further research is required to establish DOAC superiority in complicated cases, where there is clinical uncertainty.

IntroductionThe cranial cruciate ligament (CCL) is one of numerous structures which determine the path of the tibia relative to the femur when passively flexing/extending the stifle of the dog. The effect of cutting the CCL on passive motion with the hind limb in different orientations, is unknown. The aim of this study was to describe passive movement of the tibia relative to the femur in dogs, with the hind limb in three different orientations, and with CCL intact and cut.MethodsTen cadaveric hind limbs were obtained from dogs weighing between 20 kg and 25 kg and prepared for testing in a custom-built joint testing machine. Each hind limb was tested in three different orientations with data collected, using an electromagnetic tracking system, during 2 cycles of flexion/extension with the CCL intact and cut. Each cycle was initiated with the stifle in full extension (0°) and data was collected at 0°, 20°, 30°, 40°, 45°, and 55° of stifle flexion/extension.ResultsFlexion of the stifle resulted in caudal translation and internal rotation of the tibia relative to the femur, with cranial translation and external rotation occurring during extension along the identical path. Cutting the cranial cruciate ligament did not result in significant differences in translation or rotation when the stifle was orientated to approximated the standing position of a dog.DiscussionIsometric points at the origin and insertion of the CCL can potentially be identified in CCL deficient stifles using a technique based on passive motion of an intact stifle.

This study researches relationships between 12th-grade students’ epistemological beliefs towards science and their conceptual understanding of evolution by natural selection. Forty-two 12th-grade students in a suburban high school in Cyprus, who participated in a biology course, completed measures of their: (a) epistemological beliefs towards science before the intervention of being taught evolution n (b) conceptual understanding of evolution by natural selection after evolution intervention, (c) epistemological beliefs towards science after evolution intervention. Based on previous research, we hypothesised there would be a significant relationship between students’ epistemological beliefs and their conceptual understanding of evolution by natural selection after the evolution intervention. We also hypothesised that inquiry-based intervention on evolution by natural selection would foster students’ epistemological beliefs. Our results indicate that participants’ initial epistemological beliefs predict very modestly and statistically non-significant learning achievements on conceptual understanding of evolution by natural selection. However, our results show a significant improvement in participants’ epistemological beliefs after engagement in an inquiry-based intervention on evolution by natural selection. The educational significance of this and its implications are discussed.

A mode-locked, dual-wavelength pumped 3.5 <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math notation="LaTeX">$\mu$</tex-math></inline-formula> m fiber laser using frequency shifted feedback utilizing an acousto-optic modulator is reported. Pulses of 3.8 ps with 9.7 nJ were obtained at a repetition rate of 37.75 MHz. The resulting peak power is 2.55 kW. An electronically wavelength swept, mid-IR interrogator is built to characterize a mid-IR fiber Bragg grating.