Search Results (3,856)

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but may cause immune-related kidney injury, and their association with glomerular disease remains incompletely understood. We evaluated the risk of incident glomerular disease following ICI therapy using the TriNetX U.S. Collaborative Network. Adult patients with cancer treated between January 2014 and March 2025 who received ICIs were compared with those receiving conventional antineoplastic therapies after 1:1 propensity score matching for demographics, cancer type, comorbidities, medications, and baseline kidney function. The index date was constrained to an eligibility window ending 1 March 2024, and identical exposure requirements were applied to both cohorts. The primary outcome was incident glomerular disease (ICD-10-CM codes N00, N01, N02, N04, N05 and N08), and hazard ratios (HRs) were estimated using Cox proportional hazards models. The proportional hazards assumption was tested for every outcome, death was additionally modelled as a competing event, and subgroup heterogeneity was assessed by formal tests of interaction. Among 71,354 matched patient pairs, glomerular disease occurred in 2.5% of ICI-treated patients and in 2.4% of controls. ICI therapy was associated with a higher hazard of glomerular disease (HR 1.492, 95% CI 1.392–1.599). The excess hazard was concentrated in the first 500 days after initiation (interval HR 1.68); beyond approximately 1000 days, the interval point estimates approached unity. In a supporting analysis in which death was modelled as a competing event, the estimated 5-year cumulative incidence was 4.5% with ICI therapy and 3.2% with comparator therapy, an absolute difference of approximately 1.2 percentage points, and the corresponding difference in restricted mean time free of glomerular disease was about 20 days. These absolute estimates were derived from the survival functions of the matched cohort rather than from patient-level competing-risk regression and should be read as approximations. In exploratory analyses, heterogeneity was demonstrated by race, cancer type and ICI agent. Renal biopsy and urine protein testing were performed at indistinguishable rates in the two cohorts, arguing against differential detection. ICI therapy is associated with a modest absolute increase in the risk of coded incident glomerular disease, concentrated in the first 18 months, which may support targeted rather than indefinite renal surveillance. Full article

Cotton is a globally vital economic crop and the primary source of natural fiber. Continued world population growth keeps driving demand for cotton lint, while the increasing frequency of extreme weather events exposes cotton production to a range of abiotic stresses, including salinity, drought, and temperature extremes. As the very first step in plant development, the germination phase is particularly vulnerable to these stresses, which severely impair seed germination and seedling establishment through multi-faceted physiological and metabolic disruptions, ultimately compromising crop uniformity and yield potential. A thorough understanding of the underlying tolerance mechanisms holds significant potential for improving cotton germination performance under adverse conditions. However, the precise functions of stress-responsive genes and their regulatory networks during cotton germination remain largely unresolved, which restricts the targeted genetic improvement of stress resilience in breeding programs. Here we systematically review the impacts of these stresses on cotton germination and the morphological, physiological, and molecular pathways underlying stress tolerance, together with current mitigation strategies. Future research should integrate multi-omics technologies, real-time phenotyping, and controlled-environment simulations to elucidate the signal–transcription–metabolism–phenotype regulatory pathways operative during germination, thereby providing a theoretical basis for breeding stress-resilient cotton cultivars and optimizing precision sowing technologies. Full article

The automation of material receiving processes is central to ensuring traceability, process control, and data consistency in warehouse and logistics environments. This paper presents an integrated automation framework combining on-device optical character recognition (OCR), offline-first data capture, and Discrete Event System (DES) formal verification to address inbound registration failures at 3PL receiving docks. The framework comprises an Android mobile application for dock-side registration and a centralised web platform for validation and monitoring. The DES model, represented as a finite automaton, was applied pre-deployment to verify behavioural completeness, identifying three design gaps before operation began. An eight-week deployment at a Third-Party Logistics (3PL) facility showed statistically significant improvements over a two-week manual baseline (percentage points, p.p.): registration completeness +27.4 p.p. (${\chi }^2=48.0$, $p<0.001$), information gap rate −17.2 p.p. (${\chi }^2=27.1$, $p<0.001$), average registration time −56.3% ($t\left(201\right)=20.0$, $p<0.001$), and traceability coverage +57.0 p.p. (reaching 100%). The study contributes a reference architecture for inbound monitoring systems and demonstrates the practical value of DES-based pre-deployment verification. Full article

Industry 4.0 depends on the ability to connect heterogeneous systems, yet students and practitioners rarely have a low-risk environment in which to practice this kind of systems integration. This article presents a virtual-prototyping architecture developed and tested, linking a discrete-event simulation tool with external machine learning models through industrial communication protocols. The resulting artifacts and method are a contribution to systems engineering education, practice, and development. A two-phase empirical virtual-prototyping approach was used. First, Open Platform Communications Unified Architecture and Message Queuing Telemetry Transport were prototyped and compared as communication layers between Siemens Tecnomatix Plant Simulation and Python-based machine learning clients. Second, for this project, the more suitable protocol was applied to three increasingly complex use cases, addressing automated guided vehicle capacity, conveyor speed control, and process bottleneck identification. The use cases were assessed against the Technology Readiness Level scale. Open Platform Communications Unified Architecture provided reliable, real-time, bidirectional data exchange, while Message Queuing Telemetry Transport proved less stable for this application. The three use cases each demonstrated feasible simulation-machine learning integration, and the overall prototype reached Technology Readiness Level 4. Beyond its contribution to I4.0 practice, the staged research design, the use of Technology Readiness Levels as a maturity and reflection instrument, and the low-cost, risk-free nature of virtual prototyping constitute a transferable pedagogical pattern for systems engineering curricula, capstone projects, and competency-based training. Full article

The increasing demand for efficient manufacturing systems in the construction-materials industry creates a need for digital methods that enable logistics alternatives to be evaluated before physical implementation. This study applies discrete-event simulation (DES) to a real concrete paving block production system to evaluate two complementary dimensions of internal logistics improvement: logistics-system reconfiguration and coordinated resource scaling. An empirically parameterized case-study model was developed to represent mixing, vibro-pressing, curing, quality control, packaging, technological-pallet circulation, and internal transport. First, a baseline forklift-based configuration was compared with an improved configuration incorporating partial transport automation and reorganization of curing-zone material flow. In a single deterministic five-day run under identical technological assumptions, cumulative simulated output increased from 1825 to 3141 finished pallets, corresponding to a 72.1% higher output in the improved configuration. This result represents a deterministic case-scenario comparison rather than a replication-based statistical effect estimate. Second, a separate replicated resource-scaling experiment evaluated coordinated changes in forklifts, packing stations, and quality-control units. This experiment was not factorially crossed with the logistics-configuration comparison; therefore, no interaction effect between logistics configuration and resource level is inferred. The model is an offline DES decision-support representation rather than a fully integrated Digital Twin, as it does not include real-time synchronization, automatic state updating, or feedback-based control. The results demonstrate how DES can support scenario-based assessment of logistics redesign and resource-allocation decisions while making explicit the case-specific and methodological limits of the resulting performance estimates. Full article

Long-distance triathlon has become a major model for studying endurance performance. Research has nonetheless been constrained by distance-specific datasets that separate full-distance from half-distance events and largely omit transition times. Our aim was to assemble, validate, and describe an openly available dataset that removes both constraints. We compiled 2,706,922 athlete-race records from more than 1500 IRONMAN^® and IRONMAN^® 70.3 events held between 2002 and 2026, the final season partial, drawn from the official IRONMAN^® results platform (75.4%) and a third-party aggregator covering event series absent from it (24.6%). Each record contains swimming, first transition (T1), cycling, second transition (T2), running, and overall times in seconds, with finish status, age group, gender, country, and qualification points. The dataset showed close correspondence between sources and high internal consistency. Split times were identical to the second for 98.8% of 4,732,776 athlete–discipline pairs across all 559 race-years present in both sources, summed splits matched reported overall times within one second for 98.3% of records, and separated T1 and T2 times were available for 84.2% and 84.1% of records—to our knowledge, the first population-level provision of this information. Openly deposited with reproducible collection scripts, the dataset supports research on pacing, transition efficiency, sex differences, non-completion, and qualification equity. Full article

Antithrombotic therapy management in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) remains challenging as it requires simultaneous protection from cardioembolism and coronary ischemic events while minimizing bleeding. The coexistence of these competing risks, along with their different temporal profiles, has driven a major shift in therapeutic strategies over the past decade. Randomized trials have consistently shown that direct oral anticoagulant (DOAC)-based dual antithrombotic therapy (DAT) reduces bleeding as compared with prolonged triple antithrombotic therapy (TAT), supporting early aspirin withdrawal in most patients. At the same time, pooled analyses suggest that this simplification may be accompanied by a small increase in ischemic risk, particularly during the first month after PCI, when the hazard of stent thrombosis is the highest. Contemporary guideline recommendations from Europe and North America are now broadly aligned in favoring a short periprocedural course of TAT followed by DAT with a DOAC and clopidogrel, then transitioning to oral anticoagulant monotherapy. However, important uncertainty remains for patients with very high ischemic or bleeding risk, including those with acute coronary syndromes, complex PCI, prior stent thrombosis, frailty, chronic kidney disease, previous bleeding, or active cancer. In these settings, treatment decisions cannot rely solely on trial-derived estimates or isolated risk scores, but require individualized, dynamic, and phase-specific assessments. This review critically appraises the biologic rationale, randomized evidence, and contemporary guideline recommendations for antithrombotic therapy in patients with AF undergoing PCI, focusing on areas not fully resolved by current guidelines, including modulation strategies, high-risk and underrepresented populations, tailored antithrombotic management, and emerging therapeutic directions. Full article

Background: Intracranial arterial calcification (IAC), commonly detected on CT/CTA during ischemic stroke work-up, may reflect atherosclerotic burden relevant to recurrence. We evaluated whether CTA-detected IAC was associated with subsequent ischemic cerebral events. Methods: This retrospective single-center cohort included patients with ischemic stroke or transient ischemic attack admitted to a tertiary stroke unit between 2010 and 2023. IAC was assessed on index-event CTA using volumetric quantification and the Babiarz score. Time to first recurrent ischemic cerebrovascular event was analyzed using multivariable Cox regression. Robustness was evaluated through adjustment for stroke etiology and CTA acquisition parameters, penalized regression, bootstrap internal validation, and competing-risk analysis accounting for death. Results: Among 556 patients (median age, 71.5 years [IQR, 62.3–78.6]; 354 male), 60 (10.8%) experienced recurrence during a median follow-up of 3.5 years (IQR, 1.8–7.5). Median IAC volume was higher in patients with recurrence than in those without recurrence (45.0 mm³ [IQR, 14.1–143.2] vs. 18.3 mm³ [IQR, 0–105.6]; p = 0.01). A one-unit increase in log₁₀(IAC + 1), corresponding to a tenfold increase in IAC + 1, was associated with a higher recurrence hazard (HR, 1.63; 95% CI, 1.18–2.24; p = 0.003). The model had a C-index of 0.727, and the association remained consistent across sensitivity analyses. Babiarz scores correlated strongly with volumetric IAC measurements in the intracranial carotid and vertebral arteries (ρ ≥ 0.93; p < 0.01). Conclusions: Greater CTA-derived IAC burden was associated with a higher hazard of recurrent ischemic cerebrovascular events. Quantitative IAC assessment warrants further investigation as a potential imaging marker of recurrence risk, although external validation is required before clinical implementation. Full article

Drought events are expected to induce both immediate and delayed effects on tree functioning, yet the persistence and dynamics of these legacy effects remain poorly understood. In an experimental set-up, European beech (Fagus sylvatica L.) saplings were subjected to two consecutive water-withholding treatments during the 2022 growing season, resulting in five drought-severity categories. We monitored these categories over the following three years to assess drought legacy effects on phenology and growth. In the first post-drought year, bud burst proceeded more slowly in all drought categories, with the plants exposed to severe summer drought displaying the longest duration. Minor differences between drought categories and control plants were observed in timing of autumn leaf senescence in the first post-drought year and in the following bud burst, suggesting recovery in these phenological responses. Unexpectedly, differences re-emerged in autumn leaf senescence in the second post-drought year, when all drought categories displayed delayed senescence. This differentiation persisted into the following spring, with delayed bud burst in the severe spring- and summer-drought categories. The severe spring-drought categories maintained delayed senescence in the third post-drought year. Diameter and height growth were strongly reduced in the first year following drought. Although growth differences largely disappeared in the second post-drought year, the severe summer-drought categories exhibited enhanced diameter growth in the third year, indicating compensatory growth. Together, these results demonstrate that drought legacy effects in F. sylvatica are dynamically expressed over multiple years, and that such temporal variability complicates predictions of long-term forest responses to increasingly frequent episodic drought events under climate change. Full article

Background/Objectives: In high-volume gastrointestinal (GI) endoscopy units, the choice of opioid adjunct may influence awakening, post-anesthesia care unit (PACU) utilization, concomitant sedative requirements, and early cardiorespiratory events. Remifentanil has a rapid and predictable offset, whereas fentanyl may produce more prolonged residual effects. We compared postanesthetic recovery after remifentanil- versus fentanyl-based propofol sedation in routine clinical practice. Methods: This single-center retrospective cohort study included adults undergoing elective upper GI endoscopy, colonoscopy, or combined procedures under anesthesiologist-directed propofol-based sedation between 1 July 2025 and 31 January 2026. Sedation was administered according to an institutional protocol targeting a Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score of 2–3. Patients received either remifentanil or fentanyl as the opioid adjunct. The primary outcome was the interval from procedure completion to the first documented response to verbal command or purposeful awakening. Secondary outcomes included procedure and anesthesia durations, PACU length of stay, propofol and midazolam doses, and early respiratory and hemodynamic events. Stabilized inverse probability of treatment weighting (IPTW) was used to balance measured baseline characteristics. Results: Among 545 patients, 280 received fentanyl and 265 received remifentanil. All assessed covariates achieved acceptable balance after weighting. Median MOAA/S score was 2 [2-2] in both groups before and after IPTW adjustment, and target-range, deeper-than-target, and lighter-than-target MOAA/S categories did not differ significantly between groups. Weighted mean recovery time was shorter with remifentanil than with fentanyl (22.6 vs. 34.1 s; adjusted mean difference, −11.4 s; 95% CI, −13.4 to −9.5; p < 0.001). Remifentanil-based sedation was also associated with shorter procedure and anesthesia durations, shorter PACU length of stay, and lower propofol and midazolam doses; these findings remained significant after false discovery rate (FDR) adjustment. No respiratory, hemodynamic, or PACU adverse outcome differed significantly after multiplicity adjustment. Conclusions: Remifentanil-based propofol sedation was associated with shorter time to first purposeful response, shorter PACU stay, and lower concomitant sedative exposure than fentanyl-based sedation during routine GI endoscopy. Documented MOAA/S findings did not show a higher frequency of lighter-than-target clinically assessed sedation in the remifentanil group. These findings may reflect the combined contribution of remifentanil’s rapid offset and lower concomitant sedative exposure, but they should be interpreted as associations within a clinician-directed sedation strategy. The retrospective, nonrandomized design precludes causal or safety-equivalence conclusions. Full article

Psychological stress activates the local hypothalamic–pituitary–adrenal (HPA)-like axis in hair follicles, leading to cortisol overproduction and dysfunction of dermal papilla cells (DPCs). However, effective natural ingredients targeting this mechanism remain scarce. To investigate whether Camellia nitidissima flower extract (CNF) alleviates stress-induced DPC dysfunction by inhibiting 11β-Hydroxysteroid dehydrogenase type 1(11β-HSD1) and modulating the downstream signaling pathways. The phytochemical composition of CNF was characterized using HPLC-DAD. An in vitro stress-induced injury model was established in human DPCs using corticotropin-releasing factor (CRF). Cortisol levels as well as the secretion levels of hair growth factors were measured by ELISA. The expression of 11β-HSD1 was assessed via immunofluorescence. Oxidative stress was evaluated by reactive oxygen species (ROS) fluorescence and superoxide dismutase (SOD) activity. Apoptosis was analyzed by flow cytometry (Annexin V-FITC/PI). Protein expression of the TGF-β2/Smad pathway and mitochondrial apoptosis-related proteins was detected by western blotting. Cell proliferation was assessed by Ki67 immunofluorescence and cell cycle analysis. The mRNA expression of Wnt/β-catenin pathway components was quantified by Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Ten bioactive constituents, predominantly the polyphenolic compounds rutin and quercetin-7-O-β-D-glucoside, were identified in CNF. Mechanistically, CNF disrupted the local “stress-cortisol” amplification loop by first reducing CRF-induced cortisol secretion and downregulating 11β-HSD1 expression in DPCs. This upstream intervention subsequently attenuated oxidative stress and inhibited CRF-induced apoptosis via suppression of the TGF-β2/Smad2/3 pathway, while concurrently restoring proliferative capacity through reactivation of the Wnt/β-catenin signaling axis. These coordinated molecular events ultimately reinstated the secretion of key hair growth factors, including Alkaline phosphatase (ALP), Vascular endothelial growth factor (VEGF), Hepatocyte growth factor (HGF), Epidermal growth factor (EGF), and insulin-like growth factor 1 (IGF-1), thereby mitigating DPC dysfunction. Full article

Background/Objective: Long-term nucleos(t)ide analog (NUC) therapy effectively suppresses hepatitis B virus (HBV) replication, but it rarely achieves a functional cure and typically requires lifelong administration. A major unmet need in chronic hepatitis B (CHB) is the development of safe and effective strategies to discontinue NUCs without compromising viral control or hepatic safety. This exploratory, randomized pilot study evaluated therapeutic immunization in the context of discontinuation of antiviral therapy in HBeAg-negative CHB. Methods: Twenty-six HBeAg-negative CHB patients receiving long-term therapy with NUCs were randomized to either discontinue NUCs and switch to HeberNasvac (NASVAC), a therapeutic vaccine (n = 13), or receive NASVAC in addition to NUCs (n = 13). Virological, serological, biochemical, and safety parameters were assessed during a 52-week primary follow-up. In particular, ALT and AST were evaluated every 2 weeks during the first 6 months after NUC discontinuation. An extended monitoring period from weeks 96 to 192 was designed to assess virological and biochemical variables. Results: At week 48, HBV DNA remained below 2000 IU/mL in 92.3% of patients who discontinued NUCs and received NASVAC and in 100% of those who received both NUCs and NASVAC. During extended follow-up, HBV DNA < 2000 IU/mL persisted in 84.6% and 76.9% of patients in the NUC discontinuation group at weeks 96 and 192, respectively, and in 100% of patients in the continuation group (NASVAC added to NUCs) at both time points. In the first 48 weeks after NUC discontinuation, NASVAC induced a limited but significant decline in serum quantitative HBsAg. Liver function, renal, and hematological parameters remained stable, without significant ALT abnormalities, biochemical exacerbations, fibrosis progression, or severe adverse events during primary or extended follow-up. None of the patients required restarting treatment. Conclusions: NASVAC-based immunotherapy demonstrated durable virological control, a limited but progressive reduction in qHBsAg, and a strong long-term safety profile following the complete withdrawal of antiviral therapy. This exploratory study suggests that NASVAC can be administered in the context of NUC discontinuation with an acceptable short- and long-term safety profile, but controlled trials are required to determine whether therapeutic vaccination contributes independently to sustained off-treatment viral control. Full article

Process mining is a data-driven technique that acts as a bridge between data science and process management. One of its main tasks is enabling the identification of process models from event logs. However, when event logs contain sensitive data or compliance with data protection regulations is required, privacy concerns arise. To address these issues, we propose a novel process discovery method that ensures data confidentiality under an honest-but-curious scenario. Our method is the first to leverage Ring Learning With Errors (RLWE)-based encryption for process discovery, enabling computations over quantum-resistant encrypted data. Unlike existing cryptographic approaches for Privacy-Preserving Process Discovery (PPPD), the proposed method uses fully homomorphic and RLWE-based encryption to execute the required computations over ciphertexts while preserving the quality of the discovered process models. This leads to a significant reduction in execution time compared to other PPPD approaches. We evaluated our method using real-life event logs commonly employed to evaluate process discovery algorithms. The results demonstrate improved performance and enhanced privacy compared to prior approaches. This contribution represents a substantial advancement in PPPD, laying the foundation for a secure and feasible cryptographic framework. Full article

Tomato brown rugose fruit virus (Tobamovirus fructirugosum, ToBRFV) is an emerging virus that affects tomatoes, capsicum, and chili. Since its first detection in Jordan in 2015, the virus has been reported in more than 40 countries across all the continents. In Morocco, the virus was reported for the first time in October 2021. However, its genetic diversity remains unexplored. In this work, we used a collection of 100 tomato fruits from local markets to investigate the virus’s variability. Thirty-eight sequences were recovered and used to study evolutionary pressures acting on the N-terminus of the RNA-dependent RNA polymerase, the movement protein (MP), and the coat protein (CP) genes. The genetic diversity among Moroccan sequences was low, with over 99% nucleotide identity, which is consistent with the global situation, with the CP exhibiting higher diversity followed by the MP. We identified two sites with non-synonymous substitutions in the CP, and one in the MP. We used haplotype network analyses to reveal the population structure within the Moroccan isolates and studied their relationships with sequences from the rest of the world. Sequences from Morocco showed a clear geographic structure, suggesting that geographic factors, potentially combined with agricultural practices, may contribute to shaping the population structure of ToBRFV in Morocco. Our analyses suggest few introduction events, probably from Israel, Jordan, and Italy. Full article

Home insurance plays a key role in mitigating the economic and social impacts of natural disasters. This paper investigates whether the occurrence of a severe natural disaster affected the demand for home insurance in Brazil. We collect weekly sales data from the dominant insurance company with national presence, and exploit the May 2024 flood—the most severe natural disaster in the federal state of Rio Grande do Sul’s recent history—as an exogenous shock which we evaluate using Bayesian structural time-series methods (CausalImpact). We estimate that home insurance sales in Rio Grande do Sul exceeded their counterfactual by roughly 184 policies, or about 95%, over the first eight weeks following the event, while the difference is indistinguishable from zero thereafter; averaged over the full 35-week observation window, the excess is 19.6%. The timing of the response, together with additional evidence on the mechanism, is consistent with a temporary shift in the weight attached to low-probability losses rather than a lasting revision of beliefs. Full article