Abstract: Objective: To characterize the structural fragility of installed health-service capacity in Barranquilla, Atlántico, Colombia, using absolute capacity, supply concentration, reserve or transitory capacity, and service-line clinical sensitivity as structural-risk dimensions. Methods: An ecological health-services study was conducted using a local installed-capacity dataset traceable to the Colombian Special Registry of Health Service Providers and SISPRO, together with two contextual World Bank series for Colombia: physicians per 1,000 population and premature mortality from noncommunicable diseases. Traceable data cleaning, functional normalization, separation of baseline versus transitory capacity when allowed by the source fields, and exploratory estimation of a relative structural fragility proxy index using a normalized Poisson-type transformation were performed. This index was interpreted exclusively as a comparative structural-fragility ranking and not as an observed probability of saturation. Results: The analytical capacity of the Barranquilla node included 5,397 installed capacity slots. Adult ICU accounted for 707 slots and neonatal ICU for 160. Reserve capacity was low in neonatal ICU (2.5%) and higher in adult ICU (32.2%). The largest service lines were adult general hospitalization, adult ICU, and pediatric general hospitalization, whereas the highest relative structural fragility was observed in low-scale and highly concentrated services, including burn care, acute mental health, and selected highly specialized lines. Conclusion: Barranquilla has a broad but markedly heterogeneous structural health-service capacity network. The critical pattern is not determined only by the absolute number of slots, but by the interaction between limited capacity, high concentration, low stable reserve, and clinical sensitivity. The evidence generated is structural and should not be interpreted as observed occupancy, real-time saturation, or operational collapse.

Abstract: The topological properties of planetary fluids are typically analyzed by mapping classical fluid equations onto complex quantum mechanical models. Here we present a purely real, six-dimensional Stueckelberg quantum mechanical formulation of the rotating shallow water equations to demonstrate that these topological features are intrinsic to the classical kinematics itself. Operating entirely within R⁶ we decouple the complex quantum geometric tensor into an independent real Fubini-Study metric and a real antisymmetric Berry curvature. Our real-variable approach explicitly derives a topological magnetic monopole of charge C = −2 and captures the inherent scale invariance of the fluid's geometry without explicit complex coordinate representation. We suggest that continuous variations in the Coriolis parameter model the adiabatic geometric evolution of the Archean Earth, and we propose a laboratory rotating-tank experiment to physically measure this parameter sweep. Finally, we show that our real 6D formulation naturally maps to unbroken supersymmetric quantum mechanics. By identifying a purely real supercharge and calculating a fluid Witten index of W = −2, we demonstrate a strict mathematical symmetry between the topological charge of the propagating bands and the invariant of the unbroken zero-energy geostrophic vacuum. We advance the mathematically supported viewpoint that steady-state geostrophic weather patterns represent the exact supersymmetric ground states of the rotating fluid system. Consequently, the topological isolation of this vacuum naturally restricts the spectral flow across the equator, providinga theoretical explanation for the unidirectional eastward motion of equatorial boundary waves.

Abstract: Coordinated responses of intestinal epithelial and immune cells are essential for maintaining barrier integrity and immune homeostasis in dogs, yet mechanistic understanding of probiotic‑derived metabolites remains limited due to reliance on non‑canine experimental models. Here, we investigated metabolites derived from Limosilactobacillus reuteri strain ATCC PTA6127 (Lr6127), delivered as cell-free supernatants (CFS), using canine epithelial MCA-B1 cells and macrophage-like DH82 cells subjected to lipopolysaccharide (LPS)–induced inflammatory stress. Lr6127 CFS significantly reduced epithelial permeability, decreasing FITC‑dextran leakage to 94.9 ± 1.9% relative to LPS-treated controls normalized to 100% (P < 0.001), despite no detectable transcriptional changes in tight junction, adherent junction, or mucin genes. Barrier effects were instead associated with changes in markers of cellular stress re-sponses, with heme oxygenase expression reduced from 0.9 ± 0.1 to 0.7 ± 0.1 (P < 0.05). In DH82 immune cells, Lr6127-derived metabolites suppressed LPS-induced stress and inflammatory signaling, enhanced anti-apoptotic responses as reflected by increased BCL2 expression (1.4 ± 0.1 vs. 1.0 ± 0.0; P < 0.01) and elevated BCL2/BAX ratios (P < 0.01), and reduced pro-inflammatory mediators including IL-6 and CCL2 (P < 0.05–0.001). Proteomic analysis corroborated reduced abundance of inflammatory and STAT-associated signaling proteins under LPS challenge while promoting immune readiness under resting conditions. Collectively, these results suggest that Lr6127‑derived metabolites may support epithelial barrier integrity and immune re-balancing potentially through modulation of cellular stress and inflammatory path-ways.

Abstract: Background/Objectives: Acute ischemic stroke (AIS) care depends on rapid, coordinated workflows. This study compared two real-world in-hospital stroke models—a neurohospitalist-led model and a stroke practitioner–led multidisciplinary model—in terms of time metrics, radiological outcomes, and 3-month clinical outcomes in patients undergoing reperfusion therapy. Methods: This retrospective, single-center cohort study evaluated patients across two sequential workflow periods. In the practitioner-led model, trained non-neurologist clinicians coordinated care with a stroke nurse under neurologist supervision. Time metrics included door-to-needle time (DNT) and door-to-puncture time (DPT). Clinical outcomes included intensive care unit (ICU) transfer and 3-month functional outcomes assessed by the modified Rankin Scale (mRS). Results: A total of 573 patients were included (284 neurohospitalist-led, 289 practitioner-led). Baseline NIHSS scores were similar between groups. The proportion achieving DNT <60 minutes was significantly higher in the practitioner-led period (74.0% vs. 52.5%, p<0.001), while mean DNT and DPT were comparable. Early radiological outcomes at 24 hours were similar between groups. ICU transfer rates were significantly lower in the practitioner-led period (17.6% vs. 28.2%, p=0.002). Three-month mRS outcomes did not differ significantly. Conclusions: A structured, practitioner-led multidisciplinary workflow was as safe and efficient as a neurohospitalist-led model. Improved adherence to DNT targets and reduced ICU transfers highlight the importance of system-level organization in optimizing AIS care.

Abstract: Remote and hybrid work have altered where many high-skill workers live, commute, and participate in professional networks, raising new questions for technology-based economic development (TBED) in the United States. This conceptual review asks whether remote work is dispersing innovation activity, creating durable opportunities for smaller metropolitan areas, or reorganizing established geographies of advantage. The article uses a focused conceptual review that synthesizes foundational scholarship on agglomeration, clusters, and innovation geography with post-2020 research on remote work, urban restructuring, regional migration, local innovation systems, and policy responses. Sources were selected for their relevance to spatial concentration, metropolitan hierarchy, remote-worker embeddedness, and TBED strategy. The review shows that remote work has not dissolved agglomeration. Large metropolitan regions continue to concentrate remote-capable, innovation-intensive, and digitally intensive employment, while some smaller and mid-sized metros have gained visibility and mobile talent. However, the evidence points more strongly to selective gains at the margin than to broad spatial equalization. The findings also show that residential inflows alone do not create durable innovation capacity. The article argues that remote work is reorganizing rather than replacing TBED. Its central contribution is a framework of partial geographic decoupling, in which remote work loosens the routine overlap among residence, workplace, and firm location while increasing the importance of local institutions. The main policy challenge is building connective capacity that converts mobile labor into entrepreneurship, collaboration, civic participation, and long-term regional innovation. This framing clarifies how regions can compete without assuming that attracting remote workers automatically produces transformation. Recent federal and multi-survey evidence strengthens the article’s claim that remote work has stabilized above pre-pandemic levels while remaining uneven by education, occupation, and metropolitan context.

Abstract: This paper investigates bifurcation dynamics in a fractional-order extension of the classical Susceptible–Latent–Breaking–Out model for computer virus propagation. The proposed framework incorporates two distinct transmission-related time delays and employs Caputo fractional derivatives of incommensurate orders, with the delays associated with infection rate and latent period selected as the primary bifurcation parameters. Due to the combined influence of multiple delays and incommensurate fractional exponents, the resulting system exhibits a complexity that goes beyond most existing models in the literature. By linearizing the model around its endemic equilibrium and analyzing the associated characteristic roots, we characterize how the system’s qualitative behavior depends on the magnitudes of the time delays, and establish explicit sufficient conditions for bifurcation to occur. In particular, the endemic equilibrium remains asymptotically stable as long as each delay stays below a certain critical value; once any delay exceeds its threshold, the system undergoes a Hopf bifurcation, leading to sustained periodic oscillations in virus prevalence. Numerical simulations are provided to support the analytical results, and they show strong agreement between predicted and observed system responses. These findings enhance theoretical insight into bifurcation mechanisms in fractional-order delay models of epidemic dynamics on networks, and may offer useful guidance for designing containment strategies in large-scale interconnected systems.

Abstract: Endoscopic submucosal dissection (ESD) has revolutionized the management of superficial colorectal neoplasms, offering superior en bloc resection rates compared with conventional endoscopic mucosal resection (EMR). While ESD has been the standard of care in East Asian countries for over two decades, its adoption in Western countries has been considerably slower, hampered by the steep learning curve, prolonged procedural times, limited training infrastructure, and differences in disease epidemiology. However, recent years have witnessed a paradigm shift, with growing evidence from Western multicenter studies demonstrating outcomes that increasingly approach those reported from high-volume Eastern centers. The landmark RESECT-COLON randomized trial provided level-1 evidence supporting the superiority of ESD over piecemeal EMR for large colorectal polyps. Concurrently, novel training paradigms, technological innovations including traction-assisted devices and artificial intelligence (AI)-guided systems, and evolving societal guidelines from the American Gastroenterological Association (AGA), American Society for Gastrointestinal Endoscopy (ASGE), and European Society of Gastrointestinal Endoscopy (ESGE) are accelerating Western adoption. This state-of-the-art review comprehensively examines the current landscape of colorectal ESD in Western practice, highlighting the evolution of outcomes, training pathways, guideline recommendations, technological advances, and future directions. We provide a critical appraisal of the East–West outcome gap and discuss strategies to bridge this divide, positioning colorectal ESD as an increasingly viable first-line therapy for appropriate lesions in Western endoscopy centers.

Abstract: This work presents a numerical simulation study of short channel effect (SCE) in new hemispherical gate-all-around (HGAA) MOS devices. These new HGAA architectures allow optimizing the gate electrostatic control of simple GAA MOS devices after rounding their channel’s edges with well-defined radius of curvature. The simulation results indicate that the short channel effects (SCE) measured in terms subthreshold swing SS and DIBL can be significantly improved in HGAA structures with smaller silicon curvature radius. It is also found that the gate silicon surface area can be analytically calculated using the Pappus-Guldin theorem and used to model the gate oxide capacitance of such HGAA MOS devices. Pure spherical HGAA structures are also simulated and compared to simple HGAA structures, revealing their excellent performances in terms of SCE, making them ultimate 3D geometry architecture adequate for CMOS integration with the best electrostatic control.

Abstract: Dementia represents a growing global public health challenge, driving the rapid expansion of educational interventions aimed at improving awareness and promoting risk-reduction behaviours. Despite this growth, existing research demonstrates a persistent gap between knowledge acquisition and meaningful behavioural change. This paper presents a realist-informed conceptual analysis and proposes an integrative conceptual framework for evaluating the real-world effectiveness of digital dementia education. Integrating health literacy theory, the Capability–Opportunity–Motivation Behaviour (COM-B) model, and implementation science, the framework conceptualises dementia education as a dynamic, multi-component process involving resource availability, user engagement, interpretative engagement, behavioural readiness, contextual influences, and real-world outcomes. Particular emphasis is placed on interpretative engagement, grounded in constructivist and sensemaking perspectives, as a key mechanism linking exposure to educational content with behavioural intention and action. The paper identifies critical limitations in current evaluation approaches, including overreliance on knowledge-based outcomes and insufficient consideration of contextual, emotional, and implementation influences. By advancing a user-centred and context-sensitive framework, this study contributes to the development of more theoretically informed and implementation-oriented approaches for evaluating digital dementia risk-reduction education, particularly among midlife populations.

Abstract: The rapid growth of Internet of Things (IoT) ecosystems has significantly increased cybersecurity threats due to device heterogeneity, resource limitations, and exposure to distributed attacks. Although Federated Learning (FL) has emerged as a promising privacy-preserving machine learning paradigm for decentralized intrusion detection, existing FL approaches often suffer from non-independent and identically distributed (non-IID) data, communication inefficiency, adversarial attacks, and unstable convergence in heterogeneous IoT environments. This study proposes a Privacy-Enhanced Federated Learning (PEFL) framework for adaptive and secure intrusion detection in large-scale IoT networks. The framework integrated differential privacy, secure aggregation, adaptive client selection, trust-aware federated optimization, and edge-assisted hierarchical coordination to improve robustness, scalability, and communication efficiency. The framework was evaluated using benchmark cybersecurity datasets, including CICIDS2017, UNSW-NB15, TON_IoT, and Bot-IoT under heterogeneous and adversarial conditions. Experimental results established that the proposed PEFL framework achieved improved intrusion detection accuracy, faster convergence stability, enhanced resilience against poisoning attacks, and reduced communication overhead compared with conventional FL approaches such as FedAvg and FedProx. The findings further indicated that adaptive client selection and trust-aware aggregation significantly improve model reliability and robustness in resource-constrained IoT environments. This framework will contribute toward the development of scalable, privacy-preserving, and deployable federated intrusion detection systems for next-generation intelligent IoT infrastructures.

Abstract: The long-term relationship between climate change, vegetation change and soil development, is a highly complex process. Findings of multiproxy (sedimentological, MS, geochemical (AAS, XRD), micromorphological, anthracological, phytolith and malacological) studies from a loess/paleosol sequence in northeastern Hungary highlighted the transformation of a reddish-brown fossil soil layer (cambisol) to a podzolic soil with signs of iterative wildfires during the terminal part of MIS3. According to our findings, a Scots pine (Pinus sylvestris) dominated open parkland emerged on the northern slopes during the second phase of MIS3 hosted by a special reddish-brown soil. Then the last phase of MIS3 was marked by the development of spruce (Picea) dominated open parkland. Results further suggest that vegetation change passed a critical threshold leading to an unusually rapid expansion of spruce (within ca. 100 yr). This rapid expansion of spruce, changing the geochemistry of the litter to a more acidic state likely caused the initiation of podzolization and the transformation of the original soil. The opening of MIS2 marked not only intensive dust accumulation but a steady decline of arboreal elements as well leading to the emergence of a cold tundra on top of the podosol with charcoal remains.

Abstract: Brasenia schreberi is a nationally protected aquatic macrophyte of substantial ecological value and economic significance, yet its wild populations have declined drastically due to habitat degradation and anthropogenic disturbances. This review systematically synthesizes research progress on the effects of water pH and depth on the growth, ecophysiology, mucilage quality, and community structure of B. schreberi, integrating findings from field surveys and controlled greenhouse experiments to elucidate critical ecological thresholds under combined environmental stressors. Our analysis reveals that natural B. schreberi populations are predominantly distributed in lentic habitats with stable water depths of 0.5-1.5 m (optimally 1.2-1.5 m) and circumneutral to weakly acidic conditions (pH 6.0-7.5). Deviations from these parameters substantially impair plant performance: when water depth exceeds 1.5 m or pH falls below 5.5, photosynthetic efficiency declines, root-to-shoot ratios increase aberrantly, and mucilage thickness decreases significantly. The synergistic critical threshold for population decline was identified at 1.1 m depth × pH 6.3. For artificial propagation, optimal cultivation strategies diverge from wild habitat preferences: maintaining pH at 7.0-7.5 (weakly alkaline) enhances mucilage polysaccharide accumulation and commercial quality, whereas a phenological stage-specific dynamic water-depth management regime (“shallow-deep-shallow-deep”) maximizes vegetative propagation success and yield. This review provides a theoretical framework and parameterized technical guidance for wild population restoration, standardized cultivation, and hydrological regulation in plateau wetland ecosystems. Future research priorities should focus on elucidating the molecular mechanisms underlying pH- and depth-mediated mucilage synthesis, developing precision water quality management systems, and strengthening ex situ germplasm conservation.

Abstract: Smart warehouses rely on fleets of autonomous mobile robots that must continually assign tasks, plan paths, avoid collisions, and maintain battery energy. Existing lifelong multi-agent path finding studies often emphasize travel cost or makespan, while practical deployments also involve charging, payload-dependent energy use, turning and waiting costs, and congestion. This paper presents an energy-constrained hybrid repair framework for lifelong multi-agent path finding in warehouses. The method combines a risk-aware graph representation, search-based safety repair, and learning-compatible policy modules, and it is evaluated in a reproducible Python simulator. We compare independent and prioritized A* planning, windowed cooperative planning, large-neighborhood repair, lazy configuration search, bounded conflict-based search, the proposed repair variant, and a graph neural learning baseline. The virtual evaluation reports raw task completion separately from energy-feasible completion, together with collision, charger-conflict, energy, scalability, ablation, sensitivity, and case-study measures. On 40×40 warehouse maps with 20 robots, large-neighborhood repair improves raw success from 0.345 to 0.468 relative to windowed cooperative planning and reduces energy per completed task from 369.34 to 276.83. The proposed repair variant reduces several conflict measures, but throughput remains problem-dependent. The results support energy-aware repair as a practical direction for warehouse robot coordination.

Abstract: This paper presents a theoretically informed critical review of climate change discourse in Sub-Saharan Africa. Drawing on peer-reviewed scholarship and authoritative policy documents, it examines how climate knowledge is framed, communicated, authorized, and translated into public and policy use. Guided by decolonial theory and the Multiple Evidence Base approach, the review assesses climate discourse through four linked dimensions: epistemic authority, communicative accessibility, representational framing, and policy relevance. The review finds that recent scholarship and policy increasingly recognize Indigenous and local knowledge, public participation, climate education, and context-specific communication. However, significant gaps remain between formal recognition and operational integration. Climate literacy continues to vary across and within African countries; climate services become useful only when institutions align them with user needs and local decision-making contexts; and educational and policy discourse can still reproduce epistemic hierarchy even when it invokes inclusion. The paper contributes to sustainability scholarship by showing that demystification and decolonization are complementary requirements for inclusive climate governance and sustainable development. Demystification improves the intelligibility and usability of climate knowledge, whereas decolonization strengthens legitimacy by challenging hierarchies that privilege some knowledge systems while marginalizing others. A stronger climate discourse for Sub-Saharan Africa, therefore, requires institutional changes in how actors authorize knowledge, translate uncertainty, frame vulnerability and agency, and design climate communication, education, and services for public and policy use.

Abstract: Unmannedaerial vehicle (UAV)-assisted millimeter-wave (mmWave) and terahertz (THz) communications are promising enablers of ultra-reliable and low-latency communication in next-generation wireless networks. However, the initial access and beam alignment process remains challenging because highly directional beams must be rapidly aligned in a three-dimensional environment. In this paper, we investigate a risk-aware beam alignment framework for UAV-assisted mmWave/THz systems, where user equipment scans a 3D spherical region to detect UAV base stations. The objective is to jointly minimize the expected cell-search latency and its variance while satisfying detection-failure and link-quality constraints. To solve this non-convex optimization problem efficiently, we employ the Lévy Self-Renewable Flow Direction Algorithm (LSRFDA), which combines Lévy-flight exploration with self-renewal to improve convergence robustness. A unified propagation model is adopted to cover both mmWave and THz regimes by incorporating free-space spreading loss and frequency-dependent molecular absorption. Extensive Monte Carlo simulations compare the proposed approach with Particle Swarm Optimization, Random Search, Reinforcement Learning, and PPO-Lagrangian methods. The results show that LSRFDA achieves lower latency, lower latency variation, more reliable detection, and lower energy consumption across a wide range of UAV densities and coverage radii. These outcomes highlight the effectiveness of risk-aware geometric optimization for fast and dependable initial access in UAV-assisted 5G mmWave and 6G THz networks.

Abstract: This work presents a comprehensive theoretical analysis and numerical calculation of the fundamental physical parameters surrounding a non-rotating, spherically symmetric Schwarzschild black hole. Quantitative Analysis of Schwarzschild Black Hole Spacetime Radius, Light Deflection, Redshift, and Tidal Phenomena. Utilizing General Relativity, to compute the Schwarzschild radius as the defining event horizon. The gravitational time dilation, showing the dramatic slowing of time as the event horizon is approached, and the gravitational redshift of signals emitted from near the horizon. Additionally, this study calculates the relativistic deflection angle of light in the weak-field limit using the geodesic equation. To analyse the structural integrity of objects near the black hole, I have calculated the tidal acceleration and resultant tidal force, demonstrating that tidal stresses approach infinite values at the singularity, causing powerful tidal disruptions and “spaghettification”. Planetary mass black holes have a tiny size and an intense gravitational field to tear apart objects passing nearby their external surface, in contrast to supermassive black holes. These calculations provide a unified model for validating relativistic effects, offering precise quantitative measurements for astrophysical observation. Gravitational time dilation near a black hole is a profound prediction of Einstein’s general relativity, where intense gravity causes time to pass significantly slower for objects closer to the event horizon compared to distant observers. This effect means that an observer near the horizon experiences time as almost frozen from an external viewpoint.

Abstract: This study examines whether a rubric-guided large language model (LLM) can approximate local human grading practice for text-based responses in three university courses. A total of 930 student responses from Prompt Engineering, Photoshop Design, and AI Video Production were scored by two human instructors and by ChatGPT using the same five-criterion analytic rubric (Accuracy, Logical Flow, Specificity, Quality, and Originality; 0.0–3.0 each; Total 0–15). Human consensus (HC) was defined as the mean of the two human scores and was treated as a pragmatic reference rather than ground truth. Pairwise agreement among H1, H2, AI, and HC was evaluated using ICC(3,1), Pearson correlations, mean absolute error (MAE), and Bland–Altman bias and limits of agreement (LoA); a course-specific held-out calibration analysis was additionally conducted. On the Total score, human–human agreement was strong (ICC = 0.819 [0.797, 0.839]). AI–H1 and AI–H2 Total-score agreement were ICC = 0.700 [0.666, 0.732] and 0.767 [0.739, 0.792], respectively, while AI–HC agreement was ICC = 0.763 [0.735, 0.789], with MAE = 1.603 and LoA = [−4.246, 4.045]. At the trait level, AI–HC ICCs exceeded H1–H2 ICCs for all five rubric dimensions, although Quality remained weakly defined in the human baseline. On a 70/30 held-out test split, a course-specific linear calibration modestly improved Total-score ICC from 0.774 to 0.782 and reduced MAE from 1.624 to 1.215, narrowing the LoA from [−4.290, 4.188] to [−3.157, 3.329]. However, threshold-adjacent agreement remained imperfect after calibration. The findings concern written responses only and support a conservative conclusion: rubric-guided LLM scoring can assist human grading under fixed local rubrics, but the current evidence supports calibrated human–AI co-grading rather than unsupervised replacement.

Abstract: Data-driven aeration optimization is an effective approach for reducing energy consumption in wastewater treatment plants (WWTPs). However, newly established or emerging-market WWTPs often lack historical aeration logs, making it difficult to construct high-precision surrogate models. Conventional cross-plant model deployments face severe data distribution shifts, and standard multi-objective optimization algorithms are prone to generating non-physical extrapolation errors, such as achieving compliance with "zero aeration" under low-concentration conditions. To break through inter-plant data barriers, this study proposes an intelligent aeration decision-making framework that integrates cross-domain transfer learning with physics-informed constraints. First, this study designs an adversarial network based on air-to-water ratio and removal rate features. By employing a gradient reversal layer (GRL) to extract domain-invariant representations, this network achieves cross-plant knowledge transfer. Second, this study proposes a physics-informed multi-objective particle swarm optimization (PI-MOPSO) algorithm, which embeds the theoretical oxygen demand as a physical penalty into the fitness function, ensuring the physical reliability of the optimization decisions. Experiments demonstrate that the surrogate model restricts the prediction errors for effluent chemical oxygen demand (COD) and total nitrogen (TN) removal rates to within 1%. Validated by statistical tests, the improved algorithm effectively circumvents non-physical prediction biases. Its Pareto front achieves a spacing metric of 0.0027, outperforming baseline algorithms in hypervolume stability. This framework provides optimal aeration scheduling strategies conforming to biochemical dynamics for target WWTPs lacking aeration action labels, demonstrating substantial practical engineering value.

Abstract: Avian viruses formed the foundation of early retrovirology. The historical line extends from the discovery of the first sarcoma virus by Peyton Rous to the quantitative determination of oncogenic activity in cell culture by the focus assay. As a viral group, avian retroviruses offered exclusive advantages that allowed the assembly of a unique and powerful tool chest for the analysis of viral activity. Among the fundamental discoveries facilitated by these tools were viral and cellular oncogenes, cell surface receptors, virus-specific detection of inapparent infection, high-frequency genetic recombination between retroviruses, and the genetic maps of simple retroviruses. The work with avian viruses was soon complemented by research on mammalian retroviruses, and several oncogenes that became the basis of successful targeted therapies were defined. The field of cancer genes is at a point of transition. Future developments will be driven by new technologies and interpretations. They will also require a more comprehensive approach.

Abstract: Background/Objectives: Previous studies have demonstrated the safety of pre-seasonal treatment with the mannan-conjugated birch pollen allergoid EP-088-T502. However, the safety of a combined pre- and co-seasonal treatment regi-men has not yet been investigated. This study aimed to compare the safety and tolera-bility of pre-seasonal versus pre- and co-seasonal treatment with EP-088-T502. Meth-ods: In this prospective, open-label, phase III trial (T502-SIT-059) (EudraCT No.:2022-004082-20), patients (N=109) who had participated in a preceding pivotal phase III study were offered continuation treatment with active EP-088-T502 (10.000 mTU/mL) across five treatment visits. For the subgroup analysis, all patients who completed their last treatment visit before 9 April 2023 (and thus before the start of the birch pollen season in Germany) were assigned to the pre-seasonal group (N=20). Those who performed the last treatment visit thereafter were assigned to the pre/co-seasonal group (N=83). Both groups were compared in terms of local and sys-temic immediate and late phase reactions and other EP-088-T502-related adverse events (AEs). Results: No deaths nor serious adverse events (SAEs) were reported during the study. No epinephrine administration was required. Systemic adverse drug reactions (SADRs, N=3) occurred in two patients who had previously received placebo. No grade III or IV systemic reactions according to the German AWMF classification were observed. Patients receiving pre- and co-seasonal treatment developed smaller wheals (mean diameter) compared with the pre-seasonal group (immediate reactions: 0.6 vs. 0.7 cm, late phase reactions: 0.3 vs. 0.4 cm at the last treatment visit). This was also reflected in the medians (immediate reactions: 0.2 cm vs. 0.4 cm, late-phase reac-tions: 0.2 vs. 0 cm at the last treatment visit). Of all AEs that were (possibly) related to EP-088-T502 (N=89), 74 (83%) occurred at the first three treatment visits (before the birch pollen season). The frequency of AEs was comparable between groups for the last two treatment visits. Patients who had received placebo in the previous trial experienced more treatment related side effects compared to patients who had already received EP-088-T502 in the previous year. Conclusions: These data suggest that EP-088-T502 is safe and well tolerated even when administered during the birch pollen season, regardless of prior exposure to EP-088-T502.