Search Results (345)

Cycle slips, abrupt discontinuities in carrier-phase measurements, pose a significant challenge for single-frequency GNSS receivers, particularly in real-time applications where rapid detection is critical. Unlike dual-frequency approaches, these receivers cannot rely on redundant combinations to isolate slips from other errors. This study proposes a real-time cycle slip detection algorithm for single-frequency GNSS receivers based solely on short-term differencing of pseudorange and carrier-phase observables. The method employs a two-step logic: first-order differencing of code-minus-carrier and second-order differencing of carrier phase. Both steps employ satellite elevation-dependent adaptive thresholds, enabling robust detection under diverse signal conditions. The method requires no user position, receiver-generated tracking flags, or additional sensor data. Experimental results reveal that the algorithm achieves over 98% detection accuracy for slips exceeding 10 cycles, with no false positives in artificial slip testing, and 87.93% agreement with Loss of Lock Indicators (LLI) during periods in which the receiver indicated signal instability. Full article

For the correct evaluation of climate trends and climate variability, it is important to remove non-climatic biases from the observed data. Such biases, referred to as inhomogeneities, occur for station relocations or changes in the instrumentation or instrument installation, among other reasons. Most inhomogeneities are related to a sudden change (break) in the technical conditions of the climate observations. In long time series (>30 years), usually multiple breaks occur, and their joint impact on the long-term trends and variability is more important than their individual evaluation. Benova is the optimal method for the joint calculation of correction terms for removing inhomogeneity biases. Cenova is a modified, imperfect version of Benova, which, however, can also be used in discontinuous time series. In the homogenization of section means, the use of Benova should be preferred, while in homogenizing probability distribution, only Cenova can be applied. This study presents the Benova and Cenova methods, discusses their main properties and compares their efficiencies using the benchmark dataset of the Spanish MULTITEST project (2015–2017), which is the largest existing dataset of this kind so far. The root mean square error (RMSE) of the annual means and the mean absolute trend bias were calculated for the Benova and Cenova results. When the signal-to-noise ratio (SNR) is high, the errors in the Cenova results are higher, from 14% to 24%, while when the SNR is low, or concerted inhomogeneities in several time series occur, the advantage of Benova over Cenova might disappear. Full article

We report a rare case of pulmonary tumor thrombotic microangiopathy (PTTM) in a patient with metastatic neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive transverse colon cancer who exhibited a marked radiologic and biochemical response to entrectinib. Despite significant tumor shrinkage, progressive dyspnea and hypoxemia developed approximately four weeks after therapy initiation. Chest CT revealed diffuse interstitial infiltrates, initially interpreted as drug-induced pneumonitis or infection. Entrectinib was discontinued, but respiratory failure progressed, and the patient died shortly thereafter. Autopsy revealed widespread pulmonary microangiopathy with fibrocellular intimal proliferation and tumor emboli in small pulmonary arteries, consistent with PTTM. Notably, no hematogenous metastases were identified; instead, tumor spread appeared to occur via an atypical lymphatic route through the thoracic duct. The tumor exhibited microsatellite stability and a modest mutation burden, suggesting that lymphatic dissemination and microvascular pathology may progress independently of these genomic features. This case underscores a critical dissociation between oncologic response and vascular complications, indicating that tropomyosin receptor kinase (TRK) inhibitor monotherapy may be insufficient to prevent PTTM. Comprehensive management may require concurrent strategies targeting the pulmonary microvasculature, including antiangiogenic therapy and modulation of cytokine and growth factor signaling. Full article

Ice loads continue to pose challenges to the structural safety of offshore wind turbines (OWTs), while the rapid development of offshore wind power in cold regions is enabling the deployment of OWTs in deeper waters. To accurately simulate the dynamic response of an OWT under combined ice–wind loading, this paper proposes a Discrete Element Method–Wind Turbine Integrated Analysis (DEM-WTIA) framework. The framework can synchronously simulate discontinuous ice-crushing processes and aeroelastic–structural dynamic responses through a holistic turbine model that incorporates rotor dynamics and control systems. To address the issue of insufficient prediction accuracy for dynamic responses, we introduced a multivariate time series forecasting method that integrates a secondary decomposition strategy with a hybrid prediction model. First, we developed a parallel signal processing mechanism, termed Adaptive Complete Ensemble Empirical Mode Decomposition with Improved Singular Spectrum Analysis (CEEMDAN-ISSA), which achieves adaptive denoising via permutation entropy-driven dynamic window optimization and multi-feature fusion-based anomaly detection, yielding a noise suppression rate of 76.4%. Furthermore, we propose the F-Transformer prediction model, which incorporates a Frequency-Enhanced Channel Attention Mechanism (FECAM). By integrating the Discrete Cosine Transform (DCT) into the Transformer architecture, the F-Transformer mines hidden features in the frequency domain, capturing potential periodicities in discontinuous data. Experimental results demonstrate that signals processed by ISSA exhibit increased signal-to-noise ratios and enhanced fidelity. The F-Transformer achieves a maximum reduction of 31.86% in mean squared error compared to the standard Transformer and maintains a coefficient of determination (R²) above 0.91 under multi-condition coupled testing. By combining adaptive decomposition and frequency-domain enhancement techniques, this framework provides a precise and highly adaptable ultra-short-term response forecasting tool for the safe operation and maintenance of offshore wind power in cold regions. Full article

Path tracking is a fundamental challenge in the development of automated driving systems, requiring precise control of vehicle motion while ensuring smooth and stable actuation signals. Advancements in this field often lead to increasingly complex control solutions that demand significant computational effort and are difficult to parameterize. A novel variable structure path-tracking control approach that is based on the geometrically optimal solution of a Dubins car offers a promising solution to this challenge. The controller generates an n-smooth and differentially bounded steering angle, and with n + 1 parameters, it can be tuned towards performance, robustness, or low magnitude of the steering angle derivatives. In prior work, this controller demonstrated its performance, robustness, and tunablity in various simulations. In this contribution, we address the challenges of implementing this controller in a real vehicle, including system dead time, low sampling rates, and discontinuous paths. Key adaptations are proposed to ensure robust performance under these conditions. The controller is integrated into a comprehensive automated driving system, incorporating planning and velocity control, and evaluated during an overtaking maneuver (double-lane change) in a real-world setting. Experimental results show that the implemented controller successfully handles system dead time and path discontinuities, achieving consistent tracking errors of less than $0.3$ m. Full article

Hair loss (alopecia) is a common disorder caused by an interruption in the body’s cycle of hair production. This pathology negatively affects the psychoemotional state of patients and significantly reduces their quality of life. The currently available medical treatments (including minoxidil therapy) are effective in arresting the progression of the disease; however, they allow only partial regrowth of hair at best. A significant clinical result occurs only with regular drug use. There is still great interest in finding new drugs for the treatment of alopecia. In this study, we aimed to examine the effect of an aqueous dispersion of unmodified fullerene C60 (ADF) on hair growth. ADF, produced by a unique technology, is biocompatible and non-toxic. Nu/nu mice were subcutaneously injected (2 μg/animal) every two days for a period of 11 days with ADF and, for control purposes, with phosphate-buffered saline (PBS). It was shown that ADF stimulated hair growth. Histological analysis of the nu/nu mice skin areas showed that animals treated with ADF had significantly more (about twice as many) hair follicles in the anagen phase compared to mice treated with PBS. The effect on hair growth persisted even after discontinuation of ADF administration. Analysis of gene expression demonstrated that ADF affected the Wnt-signaling pathway, increased the expression of the Wnt10b (wingless-type Mouse Mammary Tumor Virus integration site family, member 10B) factor, angiogenetic factors, and downregulated tumor necrosis factor-alpha levels. We propose that the mechanism of ADF action is likely related to its ability to attract macrophages to the hair follicle microenvironment and promote their polarization to the M2 phenotype. In addition, using molecular modeling, we tried to substantiate our hypothesis about the interaction of ADF with the adenosine A2A receptor, which may cause a decrease in tumor necrosis factor-alpha production. Thus, ADF may become a promising drug for the development of new approaches to the treatment of alopecia associated with immune disorders. Full article

Diabetes is a chronic and complex pathological syndrome that includes a series of disorders and imbalances, whose first characterization is hyperglycemia, although, as it is a multifactorial phenomenon, it requires risk reduction strategies beyond glycemic control. Continuous education and support for diabetes self-management are essential to prevent acute complications and reduce the risk of long-term complications. Therefore, the guidelines for the treatment of diabetes emphasize the importance of lifestyle changes, including a reduced-calorie diet and increased physical activity. However, for many people, these changes can be difficult to maintain in the long term and eventually they must resort to pharmacological treatment that in most cases requires the combined use of two or more antidiabetic drugs with different mechanisms of action. This review explores the different pharmacological agents, authorized and used therapeutically, for the control of diabetes, especially type 2 diabetes, and analyzes the development strategies of multi-target agents whose effects, through distinct mechanisms and by acting on more than one receptor, could represent a promising alternative in the treatment of a multifactorial disease such as diabetes. As regards therapeutic uses, from metformin to glucose transporter inhibitors (SGLT2i), the potential mechanisms of action, pharmacological and clinical effects, safety, and use in therapeutics are described, presenting, as far as reasonably possible, diverse comparisons between them. In conclusion, although metformin remains the first-line agent for the treatment of type 2 diabetes, the choice of a second-line agent depends on several factors, in particular the cardiovascular risk profile, weight, and renal function of the patient; moreover, the ideal pharmacological treatment, although expected and desired, has in fact not been achieved so far, and physicians must consider not only the glycemic efficacy of the agent but also all the other potential benefits, balanced by the possible adverse effects. Compounds modulating multiple signaling pathways are a promising approach to manage this multifactorial disorder, with the primary objective of maintaining the therapeutic efficacy observed in several clinical studies, alongside reducing adverse effects, the main reason for the discontinuation of developments, to levels that enable a favorable risk–benefit balance. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, synaptic loss, and multifaceted pathology involving amyloid-β (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, and impaired proteostasis. In recent years, biologic therapies, such as monoclonal antibodies, vaccines, antisense oligonucleotides (ASOs), and gene therapies, have gained prominence as promising disease-modifying strategies. In this review, we provide a comprehensive synthesis of current biologic approaches under clinical evaluation for AD. Drawing on data curated from ClinicalTrials.gov (as of 2025), we systematically summarise the molecular targets, therapeutic modalities, mechanisms of action, trial phases, and sponsors of over 60 biologic agents. These include Aβ-directed antibodies targeting distinct conformers such as protofibrils, pyroglutamate-modified species, and soluble oligomers; tau-targeted immunotherapies and RNA-based interventions; and emerging platforms focused on neuroimmune modulation, peptide hormones, and microbiota-based strategies. Gene and RNA therapeutics, particularly ASOs and small interfering RNAs (siRNAs) delivered intrathecally or via lipid nanoparticles, are also reviewed for their potential to modulate intracellular targets with high specificity. We also analyse the historical landscape of biologic candidates that failed to reach approval, discussing key reasons for trial discontinuation, including lack of clinical efficacy, safety concerns (e.g., amyloid-related imaging abnormalities), or inadequate biomarker responses. These cases offer crucial insights for refining future drug design. Looking ahead, we highlight major challenges and evolving perspectives in AD biologic therapy: expanding therapeutic targets beyond Aβ and tau, overcoming delivery barriers to the brain, designing prevention-oriented and genetically stratified trials, and navigating regulatory and ethical considerations. Together, these efforts signal a paradigm shift in AD drug development, from symptomatic treatment to mechanism-based precision biologics. By integrating real-time clinical trial data with mechanistic insight, this review aims to inform both translational research and therapeutic innovation in AD. Full article

This study presents a smartphone-based dual-index framework for evaluating bicycle pavement conditions, aimed at supporting sustainable urban mobility and cyclist safety. Conventional assessment methods, such as the International Roughness Index (IRI), often overlook short-range discontinuities and are impractical for micromobility-scale infrastructure monitoring. To address these limitations, two perception-aligned indices were developed: the Bicycle Road Roughness Index (BRI), reflecting sustained surface discomfort, and the Faulting Impact Index (FII), quantifying acute vertical shocks. Both indices were calibrated through structured panel surveys involving 40 experienced cyclists and validated using high-frequency tri-axial acceleration data collected in both experimental and field settings. Regression analysis confirmed strong alignment between sensor signals and user perception (R² = 0.74 for BRI; R² = 0.76 for FII). A five-grade classification system was proposed, with critical FII thresholds at 87.3 m/s² for “risky” and 119.4 m/s² for “not rideable” conditions. Field validation across four diverse sites revealed over 380 hazard segments requiring attention, demonstrating the framework’s ability to identify localized risks that may be masked by traditional metrics. By leveraging off-the-shelf smartphones and open-source sensing tools, the proposed approach enables scalable, low-cost, and cyclist-centered diagnostics. The dual-index system not only enhances rideability evaluation but also supports targeted maintenance planning, real-time hazard detection, and broader efforts toward data-driven, sustainable micromobility management. Full article

For the precise description of gas physical processes in high-voltage direct current (HVDC) transmission, an advanced and robust numerical framework for the simulation of transient particle densities in the course of corona discharges is developed in this work. The aim is the scalable and consistent modeling of the space charge density under realistic conditions. The core component of the framework is a discontinuous Galerkin method that ensures the conservative properties of the underlying hyperbolic problem. The space charge density at the electrode surface is imposed as a dynamic boundary condition via Lagrange multipliers. To increase the numerical stability and convergence rate, a homotopy approach is also integrated. For the experimental validation, a measurement concept was realised that uses a subtraction method to specifically remove the displacement current component in the signal and thus enables an isolated recording of the transient ion current with superimposed voltage stresses. The experimental results on a small scale agree with the numerical predictions and prove the quality of the model. On this basis, the framework is transferred to hybrid HVDC overhead line systems with a bipolar design. In the event of a fault, significant transient space charge densities can be seen there, especially when superimposed with new types of voltage waveforms. The framework thus provides a reliable contribution to insulation coordination in complex HVDC systems and enables the realistic analysis of electrohydrodynamic coupling effects on an industrial scale. Full article

Background/Objectives: Vedolizumab is a gut-selective anti-integrin monoclonal antibody approved for the treatment of inflammatory bowel disease (IBD). While clinical trials have demonstrated a favorable safety profile, real-world studies are essential for identifying rare adverse events (AEs) and evaluating post-marketing safety. This study assessed vedolizumab’s safety in a real-world cohort and supported the detection of potential safety signals. Methods: A retrospective chart review was conducted on adult IBD patients treated with vedolizumab at a tertiary center in the Republic of Serbia between October 2021 and August 2022. Data included demographics, AEs, and newly reported extraintestinal manifestations (EIMs). Exposure-adjusted incidence rates were calculated per 100 patient-years (PYs). Disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) was performed to identify safety signals, employing reporting odds ratios (RORs) and proportional reporting ratios (PRRs) for AEs also observed in the cohort. Prior IBD therapies and reasons for discontinuation were evaluated. Results: A total of 107 patients (42.1% Crohn’s disease, 57.9% ulcerative colitis) were included, with a median vedolizumab exposure of 605 days. There were 92 AEs (56.51/100 PYs), most frequently infections (23.95/100 PYs), gastrointestinal disorders (4.30/100 PYs), and skin disorders (4.30/100 PYs). The most frequently reported preferred terms (PTs) included COVID-19, COVID-19 pneumonia, nephrolithiasis, and nasopharyngitis. Arthralgia (12.90/100 PYs) was the most frequent newly reported EIM. No discontinuations due to vedolizumab AEs occurred. FAERS analysis revealed potential signals for events not listed in prescribing information but observed in the cohort: nephrolithiasis, abdominal pain, diarrhea, malaise, cholangitis, gastrointestinal infection, blood pressure decreased, weight decreased, female genital tract fistula, respiratory symptom, and appendicectomy. Most patients had received three prior therapies, often stopping one due to AEs. Conclusions: Vedolizumab demonstrated a favorable safety profile in the IBD cohort. However, FAERS-identified signals, such as nephrolithiasis, gastrointestinal infections, and decreased blood pressure, warrant further investigation in larger, more diverse populations. Full article

Belzutifan is a hypoxia-inducible factor-2α (HIF-2α) inhibitor that received FDA approval in 2021 for treating cancers resulting from von Hippel-Lindau (VHL) disease, including clear cell renal cell carcinoma (ccRCC), followed by approval in 2023 for sporadic ccRCC that has progressed through multiple lines of therapy. HIF-2α is a promising drug target, as VHL is commonly inactivated in ccRCC, which results in HIF-2α-mediated signaling that is considered central to tumorigenesis. Belzutifan has demonstrated efficacy in clinical trials in the first-line and subsequent line settings, and in combination with tyrosine kinase inhibitors. Despite being overall well tolerated, belzutifan has a distinct safety profile because of its unique mechanism of action. Anemia was the most common adverse event observed in clinical trials and is considered an on-target effect. Hypoxia is also frequently observed and commonly results in dose reductions, treatment discontinuation, and supplemental oxygen use. This review summarizes the rates of hypoxia seen in clinical trials of belzutifan in ccRCC. As the cause of hypoxia is not well understood, this review also discusses possible mechanisms of hypoxia based on preclinical studies of the HIF pathway and HIF-2α inhibitors. Finally, this review proposes monitoring and management recommendations for clinicians prescribing belzutifan to ccRCC patients. Full article

Localization is one of the essential problems in the Internet of Things (IoT). Dynamic changes in the radio environment may lead to poor localization accuracy or discontinuous localization in non-line-of-sight (NLOS) scenarios. To address this problem, this paper proposes a localization enhancement method based on direct-path identification and tracking. More specifically, the proposed method significantly reduces the range error and localization error by quickly identifying the line-of-sight (LOS) to NLOS transition and effectively tracking the direct path. In a large testing hall, localization experiments based on the ultra-wideband (UWB) signal have been carried out. Experimental results show that the proposed method achieves a root mean square localization error of less than 0.3 m along the user equipment (UE) movement trajectory with serious NLOS propagation conditions. Compared with conventional methods, the proposed method significantly improves localization accuracy while ensuring continuous localization. Full article

The Qiangtang Basin (Tibetan Plateau) poses significant geophysical challenges for seismic exploration due to near-surface widespread permafrost and steeply dipping Mesozoic strata induced by the Cenozoic Indo-Eurasian collision. These seismic geological conditions considerably contribute to lower signal-to-noise ratios (SNRs) with complex wavefields, to some extent reducing the reliability of conventional seismic imaging and structural interpretation. To address this, the common-reflection-surface (CRS) stack method, derived from optical paraxial ray theory, is implemented to transcend horizontal layer model constraints, offering substantial improvements in high-SNR prestack gather generation and prestack depth migration (PSDM) imaging, notably for permafrost zones. Using 2D seismic data from the basin, we detailedly compare the CRS stack with conventional SNR enhancement techniques—common midpoint (CMP) FlexBinning, prestack random noise attenuation (PreRNA), and dip moveout (DMO)—evaluating both theoretical foundations and practical performance. The result reveals that CRS-processed prestack gathers yield superior SNR optimization and signal preservation, enabling more robust PSDM velocity model building, while comparative imaging demonstrates enhanced diffraction energy—particularly at medium (20–40%) and long (40–60%) offsets—critical for resolving faults and stratigraphic discontinuities in PSDM. This integrated validation establishes CRS stacking as an effective preprocessing foundation for the depth-domain imaging of complex permafrost geology, providing critical improvements in seismic structural resolution and reduced interpretation uncertainty for hydrocarbon exploration in permafrost-bearing basins. Full article

HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2/SOD cascade and inhibition of the HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK/ULK1/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis. Full article