Abstract: Background: Good Pharmacy Practice (GPP) provides a globally recognized framework to promote the safe, effective, and rational use of medicines while strengthening the role of pharmacists in patient-centered health care. To enhance awareness and practical understanding of GPP principles in the local context, a one-day workshop titled “GPP: Strengthening the Role of Pharmacists in Health Care Delivery” was conducted. Methods: The workshop was facilitated by subject experts and faculty members and included focused presentations and interactive discussions addressing key components of GPP, such as rational use of medicines, medication counseling, professional ethics, and the evolving responsibilities of pharmacists. Particular emphasis was placed on the current status, challenges, and opportunities for GPP implementation in Nepal in comparison with international standards. Participant feedback was collected at the end of the program. Results: Participants reported a high level of satisfaction with the workshop, highlighting the relevance and clarity of the content as well as its perceived professional and career-related benefits. Interactive discussions enabled participants to identify context-specific challenges and opportunities in pharmacy practice in Nepal. Minor logistical limitations, including sound system and internet connectivity issues, were noted but did not significantly affect overall engagement. Conclusion: The workshop underscored the importance of continuous professional development initiatives to strengthen the implementation of GPP and enhance pharmacists’ contributions to health care delivery. Conducting similar capacity-building programs, particularly in remote and underserved regions, may support the promotion of standardized pharmacy practice and contribute to improved health care outcomes in Nepal.

Abstract: Numerous adverse effects caused by oxidative stress are commonly observed in preterm infants. This stress is caused by the oxidative burden resulting mainly from supplemental oxygen and parenteral nutrition (PN), and by their precarious antioxidant defense system. The natural antioxidant defense against these oxidant molecules relies on glutathione, levels of which are low in preterm infants. Given that several short- and long-term biological complications, including lung damage, are associated with this oxidative stress, the aim of this review was to discuss possible methods for reducing it. Consequently, after briefly discussing the effectiveness of reducing oxidative stress-related effects achieved through adequate photoprotection of PN, it is proposed to correct glutathione deficiency by adding glutathione to PN intended for premature infants. This article addresses the 1) importance and efficacy of parenteral glutathione in preventing oxidative stress, 2) causes of glutathione deficiency and ways to prevent it, 3) reasons why the disulfide form (GSSG) is recommended over the reduced form (GSH) for enriching PN, and 4) safety profile of glutathione infusion. In conclusion, we believe that the time has come to improve the health of premature infants by providing them with GSSG supplemented PN that is adequately photoprotected.

Abstract: We develop a unified first-order framework for relativistic fields of different spin, in which the dynamics are governed by a common operator-based equation. This formulation provides a coherent description of scalar, spinor, vector, and tensor fields within a single structure and reproduces the corresponding second-order wave equations in appropriate limits. A central result is the emergence of a consistent spin-2 sector from the same underlying dynamics. By constructing the tensor field as a bilinear combination of internal spacetime degrees of freedom, we obtain a symmetric rank-2 field with the correct number of independent components. In the massless limit, the resulting equation matches the structure of linearized gravity, while source-like terms arise naturally from quadratic combinations of field derivatives, providing an intrinsic origin for an effective energy–momentum tensor. The Lagrangian formulation yields conserved quantities via Noether’s theorem and reproduces derivative structures consistent with the weak-field Einstein–Hilbert action. These results suggest that gravitational dynamics may emerge from a more fundamental first-order field theory.

Abstract: During atmospheric reentry, a spacecraft is enveloped by a turbulent plasma sheath that induces severe signal degradation and communication blackout. Conventional mitigation strategies primarily focus on reducing average attenuation but fail to address the dynamic fluctuations in plasma density (typically 20%–40%), which cause significant group velocity dispersion (GVD), pulse broadening, and intersymbol interference. To overcome this limitation, this paper proposes an active decoupling framework that dynamically tunes an external magnetic field to suppress turbulence-induced signal distortion in the reentry plasma sheath. By establishing a wave propagation model for right-hand circularly polarized (RCP) waves in magnetized collisional plasma and introducing a sensitivity analysis of propagation parameters with respect to plasma density fluctuations, we derive the condition under which the first-order sensitivity of GVD vanishes. Under this condition, a dynamic balance between collisional effects and frequency detuning renders the system immune to density perturbations, effectively decoupling signal transmission from plasma turbulence. Numerical simulations demonstrate that, under optimal parameter matching, pulse broadening is suppressed by several orders of magnitude, and the broadening factor remains near unity over extended propagation distances. Furthermore, reentry trajectory analysis reveals that static matching is insufficient in dynamically evolving environments, motivating the necessity of adaptive magnetic field control. This work provides a novel physical-layer paradigm for mitigating reentry blackout by actively decoupling signals from turbulence via dynamically tuned magnetic fields.

Abstract: Background: Heme oxygenase (HO) is an antioxidant enzyme ubiquitously present in the body. Oxidative stress is one of the main causes of male infertility. Here, we aimed to analyze the correlation between serum heme oxygenase-1 (HO-1) level and sperm count, motility, normal morphology, and sperm DNA fragmentation index (DFI) in infertile male patients. Methods: In this retrospective cross-sectional study, serum HO-1 concentrations, routine semen parameters, sperm morphology, and DFI were analyzed in 178 patients. Subjects were stratified into high-HO-1 (≥278 ng/L; n=77) and control (<278 ng/L; n=101) groups. Intergroup comparisons and Spearman's correlation analyses were performed. Results: The high-HO-1 group demonstrated significantly increased normal sperm morphology (P<0.05) and reduced sperm DFI (P<0.05) versus controls. No significant intergroup differences existed in sperm concentration or progressive motility (P>0.05). Correlation analysis revealed positive associations between HO-1 levels and normal morphology (r=0.190, P<0.05), and negative correlations with DFI (r= -0.195, P<0.05).Conclusions: We first identified significant correlations between serum HO-1 levels and both sperm DFI and normal morphology in infertile men, suggesting HO-1's protective role in spermatogenesis. Serum HO-1 quantification may offer a novel strategy for male fertility assessment.

Abstract: In this paper, we are concerned with the existence of crossing periodic solutions for a class of second order discontinuous undamped Duffing equations. By applying the Poincaré-Bohl theorem, we obtain several existence results of 2π crossing periodic solutions.

Abstract: Healthy and sustainable food consumption implies not only making conscious food choices but also limiting waste. In fact, interventions targeting choices are effective only if the healthier food selected is not wasted on the plate. The aims of the study were: to quantify plate and service waste in hospital canteens; to characterize plate waste (PW) composition and environmental indicators; to compare PW before and after an intervention to improve food choices. Trays of users who gave consent were photographed (N=1,624) in three hospital canteens in Italy. PW was quantified visually, and energy, nutrients, and environmental indicators were estimated using portion sizes and recipes provided by canteen staff. PW was 4.7% (2.0-6.1% by canteen), corresponding on average to 33.1 g/tray, 43.6 kcal/tray, 69.6 gCO2 eq./tray and 61.8 LH2O/tray. Side dishes contributed the most to total PW (30%). The canteen where PW had decreased significantly (median among wasters: -48.9 g/tray) was the one with the poorest result in food choices. PW increased, though not significantly, in the other two canteens. Service waste analysis revealed considerable variability, probably driven by canteen management. In conclusion, the present study highlights the importance of including plate and service waste in public health campaigns.

Abstract: In the context of SDG 7 and SDG 13 of the 2030 sustainable development agenda, a new performance indicator started to gain momentum in scientific research: the renewable energy productivity. Understanding the drivers and the challenges of green energy productivity could help add on to the classical focus of renewable energy research on infrastructure, technical and economic feasibility, environmental and social impacts, by considering more the performance indicators in this field. Only very few studies explored the influencing factors of the renewable energy productivity. Thus, this research aims to reveal the impact of social, economic, energy, and environmental variables on the green energy productivity. The methodological approach involves bibliometric analyses of the literature on green energy productivity (GEP), and panel data regression models involving 16 independent variables. The main findings indicate positive effects of green taxes, female participation in the workforce, and highly educated people on GEP, pointing out the importance of green taxation, education, and gender equality in sustainable development. On the other side, negative relationships of green energy productivity with economic growth, traditional energy variables, and air pollution were found for the European Union’s member states over 2007 and 2023. The results suggest that the analyzed European countries based their economic growth on traditional resources, with less importance provided to the renewable resources and green technologies, as the share of renewable resources of GDP was also negatively correlated. While private financial resources increases the green energy productivity, questions about research and development investments, urbanization, and diversity index are still debatable.

Abstract: Achieving carbon neutrality has become a central policy objective for emerging economies, particularly the BRICS countries-BRICS (Brazil, Russia, India, China, and South Africa) which collectively account for a substantial share of global carbon emissions and energy consumption. The transition toward green energy, rapid technological innovation, and the expansion of green finance mechanisms are increasingly viewed as critical drivers of sustainable development and environmental improvement. However, empirical evidence integrating these three dimensions within a unified analytical framework for BRICS remains limited. This study examines the contribution of green energy transition, technological innovation, and green finance to achieving carbon neutrality in BRICS countries using a Pooled mean group auto regressive distributed Lag (PMG ARDL) framework and Dumitrescu–Hurlin panel causality analysis. The results indicate that green energy transition significantly reduces carbon emissions in both the long run (−0.45) and short run (−5.65), emphasizing the importance of shifting toward renewable energy sources. Technological innovation exerts a significant negative effect in the long run (−0.17), reflecting efficiency gains and cleaner production, although its short-run impact remains insignificant. Similarly, green finance improves environmental quality in the long run (−0.10) by supporting low-carbon investments, while short-run effects are statistically insignificant due to adjustment frictions. Economic growth increases emissions in the long run (0.43), confirming the scale effect, whereas trade openness reduces emissions (−0.87), indicating the role of technology diffusion. The error correction term (−0.76) confirms a strong convergence toward long-run equilibrium. The causality analysis reveals unidirectional causality from green energy transition, technological innovation, and green finance to carbon emissions, while bidirectional causality exists between economic growth and emissions, highlighting a feedback mechanism. Policy implications suggest that BRICS economies should strengthen green financial systems, accelerate renewable energy adoption, promote innovation-driven sustainability, and design growth strategies that decouple economic expansion from environmental degradation.

Abstract: Sanitation knowledge, attitudes, and practices (KAP) among primary school learners can aid in disease prevention through sanitation as well as in improving learner academic achievement. Despite this, evidence regarding sanitation KAP among rural South African primary school learners is inadequate. In this study, sanitation KAP among grade 6 learners in Sekhukhune District, Limpopo Province, were investigated. The study adopted a quantitative cross-sectional design among 249 learners chosen randomly from nine primary schools. Data were collected utilizing a structured questionnaire which was pre-tested prior to the study. Analysis was performed using SPSS version 29 with the help of the Pearson chi-square test at a significance level of 5%. Of the total sample size, 59.0% exhibited adequate knowledge about sanitation (≥80% correct answers). Nonetheless, 41% held erroneous views regarding hand washing that it was enough for hands to look clean even without the use of soap, while only 41.0% used soap always after defecating. Open defecation was noted by 12.4% of the learners, where non-functional toilets accounted for 73% of these cases. Over half (45.8%) of the respondents were embarrassed about using school toilets. Knowledge about ill effects of poor hygiene on one's health correlated significantly with the age of learners.

Abstract: Background: Effective pharmacy regulation is a cornerstone of patient safety and rational medicine use. In Nepal, despite the existence of regulatory frameworks such as the Drug Act 2035 and policies restricting non-prescription sales of antibiotics, enforcement is weak and inconsistent, leading to widespread regulatory failure in community pharmacies. Problem: Multiple studies have documented widespread dispensing of antibiotics without valid prescriptions in community pharmacies across Nepal, with non-pharmacist staff frequently engaging in these practices. Analysis: Policy and practice gaps in Nepal’s pharmacy sector reflects systemic issues including insufficient regulatory capacity, workforce shortages of qualified pharmacists, market-driven dispensing behaviors, and low public awareness of rational medicine use. These structural barriers continue unsafe pharmaceutical care and weaken pharmacovigilance systems. Policy Implications: Strengthening enforcement must be reframed as a health systems and patient safety priority rather than a narrow regulatory task. A multi-pronged strategy including mandatory qualified pharmacist presence, enhanced inspection and compliance monitoring, integration of community pharmacies into national antimicrobial stewardship programs, and public awareness campaigns is urgently needed. Conclusion: Weak enforcement of pharmacy regulation in Nepal constitutes a significant but under-recognized threat to patient safety and antimicrobial stewardship. Translating existing policies into practice through systemic reforms can reduce medication-related harm and preserve antibiotic effectiveness.

Abstract: Background: Polyphenols interact bidirectionally with the gut microbiota and may enhance short‑chain fatty acid (SCFA) production, yet evidence from human randomized controlled trials (RCTs) has not been comprehensively synthesized. Objectives: This systematic review and meta‑analysis evaluated the effects of polyphenol supplementation on gut microbiota composition, microbial diversity, and fecal SCFA concentrations in adults, and examined moderators of these effects. Methods: Five databases were searched through October 2023 for RCTs assessing oral polyphenol supplementation in adults. Eligible studies reported outcomes related to gut microbiota composition or fecal SCFAs. Random‑effects meta‑analyses were conducted for SCFA outcomes, and subgroup analyses examined effects by polyphenol class, dose, duration, health status, and analytical methods. Risk of bias was assessed using the Cochrane RoB 2 tool, and certainty of evidence using GRADE. Results: Fifty RCTs (n = 2,042 participants) were included. Polyphenol supplementation increased total SCFAs in 70.6% of studies and significantly increased butyrate concentrations (pooled SMD = 0.48; 95% CI: 0.32–0.64; I² = 58%). Acetate and propionate increased in 75% and 71.4% of studies, respectively. A consistent shift toward a more butyrogenic fermentation profile was observed. Polyphenols enriched beneficial genera, including Bifidobacterium (81.8%), Akkermansia muciniphila (50%), and Faecalibacterium prausnitzii (45.5%), while reducing potentially pathogenic taxa such as Enterobacteriaceae and Clostridium spp. Improvements in alpha diversity were reported in 66.7% of studies, and beta diversity separation in 87.5%. Effects were stronger in individuals with metabolic disorders and in interventions lasting ≥12 weeks. Conclusions: Polyphenol supplementation consistently enhances beneficial gut bacteria, increases SCFA production, particularly butyrate, and improves microbial diversity in adults. These findings support classifying polyphenols as bioactive prebiotics that meet ISAPP criteria. This term underscores their distinction from traditional prebiotics within our proposed five-phase model: whereas fibers are characterized by their fermentability, polyphenols integrate direct antimicrobial activity against pathogenic species (e.g., Staphylococcus aureus, Enterobacteriaceae) with their role as selective substrates for beneficial microbes. This dual mechanism of action suggests that polyphenols do not merely supplement the microbiota but actively reshape it by pruning harmful taxa while fertilizing beneficial ones. Polyphenol-rich strategies represent promising microbiota-focused approaches; however, while shifts in microbial profiles coincide with better metabolic health, further research is required to bridge the correlation-causation gap and confirm whether these microbial changes directly drive clinical outcomes.

Abstract: Events such as landslides and slope failures happen suddenly and can be catastrophic. To predict the onset of such events, as well as the flow and final deposition of the material, engineers make use of numerical modeling techniques. These events are associated with large deformation and mesh-based methods, such as the finite element method, are not capable of modeling them due to mesh distortion. The material point method (MPM) is a particle-based continuum method capable of modeling large deformation and material flow. In this paper, MPM is used to model the sudden and dynamic flow of material by modeling the collapse and runout of a non-cohesive sand column. The results from two- and three-dimensional models are compared to experiments, showing that MPM accurately predicts the free-surface profile of the material during collapse. Furthermore, the model accurately predicts the runout distance with an error of less than 5%.

Abstract: How life originated in the ancient abiotic world is one of the most fundamental questions in modern bioscience. To address this problem, I propose a scientifically credible, fact-based scenario involving a pre life molecular entity that ultimately gave rise to living organisms. This entity consisted of DNA and RNA, in which double stranded linear DNA replicated in a calm environment with the assistance of RNA and served as a stable repository of information essential for evolution and survival. In the same environment, RNA molecules with catalytic activity replicated exclusively in stem–loop forms and gave rise to ribosomal and transfer RNAs. Under such calm, ribonucleotide rich conditions, the information stored in double stranded linear DNA was transcribed into messenger RNA. The seemingly improbable emergence of the extraordinarily complex translational system is hypothesized to have occurred through extended wobble-based recognition of all messenger RNA triplets by only two prebiotic tRNAs, enabling protein synthesis. Finally, independently evolved rRNA and tRNA are proposed to have been abiotically reverse transcribed and integrated into DNA based entities in a calm, deoxynucleotide rich environment. Thus, DNA and RNA are functionally interdependent: DNA stores genetic information encoding essential RNAs and produces self-beneficial protein products, whereas information stable double stranded DNA relies on RNA for its replication and transcription, particularly in calm prebiotic environments. This mutual dependence establishes a self-sustaining molecular system capable of problem solving, thereby enabling the emergence and evolution of life.

Abstract: To alleviate the shortage of natural river sand and promote the utilization of aeolian sand, concrete was prepared by replacing river sand with Taklamakan Desert aeolian sand at different mass ratios. The effects of replacement ratio and curing age on compressive strength and microstructure were investigated using compressive strength tests, SEM, and EDS. A quadratic regression model was established by response surface methodology using replacement ratio, curing age, and Ca/Si ratio as variables. The results showed that compressive strength first increased and then decreased with increasing aeolian sand content, with the 20% replacement group achieving the highest strength. Strength increased with curing age, but the growth rate slowed after 28 days. SEM and EDS results indicated that suitable aeolian sand content promoted hydration product formation and matrix densification, whereas excessive replacement increased pores and interfacial defects. The Ca/Si ratio generally increased with curing age. The model showed good fitting accuracy, with R² = 0.9970, providing a reference for strength prediction and mix design optimization of aeolian sand concrete. Keywords: aeolian sand concrete; compressive strength; microstructure; Ca/Si ratio; response surface methodology

Abstract: Background/Objectives: Endodontic success in maxillary first molars is often complicated by their complex anatomy, increasing the risk of procedural errors in "danger zones" where dentine is thin. While global data on root morphology exists, population-specific information for South Africans is lacking. This study aims to quantify root dentine thickness in a Black South African sample using a novel software program to enhance accuracy for preoperative planning and improved clinical outcomes. Methods: Micro-CT scans of 97 maxillary first molars (57 individuals) were analyzed. Den-tine thickness was measured at 0.1 mm intervals using a novel surface-to-interface software tool, which enabled automated, high-precision quantification of complex curved geometries. Data were standardized into 1 mm segments for analysis. Reliability trials confirmed high precision (within 0.0001 mm). Results: Buccal and lingual surfaces of mesiobuccal and distobuccal roots were consistently thicker than mesial and distal surfaces. All roots showed progressive thinning toward the apical third. Conversely, palatal roots exhibited an opposing pattern with mesial and distal surfaces that were thicker than buccal and lingual aspects. Age correlations were not statistically significant. Conclusions: The study identifies specific anatomical patterns in root dentine thickness within a South African sample. The thinner mesial and distal walls of buccal roots represent critical "danger zones" for clinicians. The novel software proved highly effective for precise morphometric mapping and offers a versatile framework for broader endodontic research. These findings provide essential data for optimizing endodontic treatment strategies and the development of population-specific dental instruments.

Abstract: This paper introduces the Generalized Coordinate System (GCS) as a framework for analyzing and generating rhetorical modes---the conventional patterns of discourse. The GCS is composed of low-dimensional, mediating and high-dimensional axes. The low-dimensional axes are Thing, Feature, Quantitative Attribute, Qualitative Attribute, Formal Attribute axes and form the objects or foundational elements for rhetorical modes. The mediating axes are Basic Expressive-Representational Elements and Rhetorical Mode axes and transform the raw material into communicable languages. The high-dimensional axes include Cognitive Function axis, Epistemic Purpose axis and the Five-Level Expression Staircase axis (Depth axis). The high-dimensional axes determine the cognitive depth and ultimate purpose, and capture the developmental progression of language competence- from raw perception to paradigm-shattering insight. Three types of semantic or modal mapping are defined: low-dimensional mapping (from low-dimensional axes to the mediating axes), high-dimensional mapping (from the mediating axes to high-dimensional axes), and full-dimensional mapping. These mappings form a pyramidal hierarchy, progressing from foundational elements (things, features, and attributes) to higher-order cognitive functions and epistemic purposes. By employing three core logical structures---combinatory, parallel, and embedded---the GCS consolidates infinite expressive possibilities within the finite intersections of its axes. The system's generative capacity, quantifiable by the number of axis intersections (generalized mode number), enables the navigation of nearly infinite expressive variations while steering practical applications toward finite, purpose-driven goals. The GCS transitions rhetorical modes from a static taxonomy to a dynamic analytical system for discourse construction and analysis, offering possibly insights for the development of large language models through the integration of a programmable rhetorical mode system.

Abstract: Recent research in cancer detection and monitoring is based on the development of multi-agent systems. They are used for multidimensional multimodal health data integration, medical data augmentation, knowledge representation, predictive diagnosis, and personalized treatment schemes. This paper addresses the last two challenges by introducing intelligent agents to build clustering, classification, and treatment-recommendation models, while also improving overall process time through feature selection and the identification of critical malignant cases. In the first stage, the Wrapper Selection Agent based on Random Forests generated an optimized model with a 98.68% accuracy. Then, the Outlier-based Clustering and Critical Malignant Cases Agents detected the critical malignant cases with a 0.84 Silhouette Score. In the next step, Treatment Clustering and Decision Rules Agents built a perfect model that proposes a personalized treatment for the patients identified by the previous agents. The entire process is automated and provides treatment recommendations in 32.85 seconds.

Abstract: Background: The adaptogen concept, first formalized over half a century ago, describes pharmacological agents that increase nonspecific resistance to stress. Despite extensive clinical evidence supporting the efficacy of adaptogenic botanicals, the concept has re-mained largely phenomenological, lacking a mechanistic framework compatible with modern molecular pharmacology. This has limited its acceptance in evidence-based medi-cine. Aims: We propose that hydroponically cultivated red Panax ginseng preparation HRG80, with its chemically reproducible composition and multilevel evidence base, constitutes a case study through which the mechanistic basis of adaptogenic action can be examined across molecular, cellular, neurophysiological, and clinical levels. Methods: We identified all published preclinical and clinical studies conducted on HRG80 through PubMed, Scopus, and manual citation tracking (last search: March 2026). Ten published studies met the inclusion criterion, including three randomized, dou-ble-blind, placebo-controlled clinical trials and two open-label trials, encompassing ap-proximately 440 human subjects. One manuscript in preparation and one unpublished preclinical gut-brain axis dataset were included with appropriate caveats. We integrated transcriptomic, electrophysiological, in vitro, in vivo, and clinical evidence into a pro-posed mechanistic model. Results: The converging evidence supports a three-tier temporal model of adaptogenic ac-tion. The acute tier (minutes to hours) involves modulation of NMDA and Kainate gluta-mate receptors, enhancing hippocampal long-term potentiation. The subacute tier (days to weeks) involves activation of CREB signaling and the slit-robo axonal guidance pathway, producing structural neuroplasticity functionally equivalent to brain-derived neu-rotrophic factor stimulation. The chronic tier (weeks to months), based on in vitro evidence in non-neuronal models, involves DNMT inhibition and epigenetic reprogramming, sug-gesting a potential mechanism for durable changes in cellular stress resilience. Tran-scriptomic analysis identified 1,061 genes uniquely modulated by the whole extract and not by isolated ginsenosides, consistent with the hypothesis that the adaptogenic effect is an emergent property of the phytochemical network. Preliminary preclinical data from a gut-brain axis model suggest that HRG80 protects intestinal barrier integrity and attenu-ates neuroinflammation, providing a plausible systemic pathway from oral intake to cen-tral effects. Conclusion: HRG80 provides convergent multilevel evidence suggesting that adaptogenic nonspecificity may reflect a hierarchically organized multi-specificity operating across distinct temporal scales. If confirmed by independent replication and further mechanistic studies, this framework could offer a template for the systematic investigation of other adaptogenic botanicals.

Abstract: Background and Objectives: Chronic diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) remain a major source of morbidity, healthcare utilization, and limb loss, despite adherence to established standards of care protocols and the widespread availability of advanced wound technologies. Many advanced modalities only target isolated aspects of wound healing and fail to address the complex, interdependent pathophysiology of chronic wounds, particularly tissue hypoxia, edema, impaired microcirculation, and persistent inflammation. Cyclical Pressurized Topical Wound Oxygen (TWO2) therapy is a home‑based, multimodal intervention that combines humidified topical oxygen delivery with cyclical non‑contact compression to address these core drivers simultaneously. Materials and Methods: This review synthesizes mechanistic rationale and evidence from randomized controlled trials, long-term venous ulcer studies, and real-world comparative effectiveness analyses. Emphasis is placed on the large cohort study by Yellin et al., which directly compared TWO2 with other advanced modalities including negative pressure wound therapy (NPWT), skin substitutes, and growth factor therapies. Results: Across these studies, TWO2 therapy is consistently associated with improved healing durability, reduced recurrence, and substantial reductions in hospitalization and amputation rates compared with both standard care and advanced wound therapies. Conclusions: The convergence of randomized and real‑world evidence supports TWO2 therapy as a clinically meaningful and mechanism‑driven adjunctive treatment option for patients with chronic, high‑risk lower‑extremity wounds.