Overweight and obesity is a prevalent and growing global health concern associated with a significant healthcare burden. With recent advancements in weight management interventions demonstrating cardioprotective benefits, there is a need for risk equations that can accurately predict cardiovascular event risk in health economic models to support healthcare decision making and resource allocation. We aimed to derive risk equations using SELECT trial data that estimate the risk of acute coronary syndrome and stroke in people with established cardiovascular disease and overweight or obesity but without diabetes mellitus for use in health economic modelling. Risk equations estimating first in-trial observed acute coronary syndrome and stroke were derived from patient-level data from the SELECT trial, a double-blind randomised placebo-controlled trial comparing semaglutide 2.4 mg with placebo. Risk factors were identified from the literature and by clinical experts. Risk equations were developed using cause-specific Cox proportional hazard models with all-cause mortality as a competing risk. Least absolute shrinkage and selection operator (LASSO) penalisation was applied 100 times in bootstrap samples to refine the risk equations. Final risk equations were validated with clinical experts and using SELECT trial data. Sex, coronary heart disease, a history of acute coronary syndrome and use of angina medications had the strongest associations with acute coronary syndrome (hazard ratio 1.67-1.82). For stroke, a history of atrial fibrillation, cerebrovascular disorder, stroke and transient ischaemic attack had the strongest associations (hazard ratio 1.40-1.70). In terms of discrimination, the risk equations had an area under the receiver operating characteristic curve (AUC) of 0.66-0.68 for acute coronary syndrome and 0.68-0.71 for stroke, and C-indices of 0.67-0.69 for acute coronary syndrome and 0.66-0.69 for stroke. The risk equations showed good cohort-level predictive capabilities over a 4-year time horizon. These novel, treatment-specific, trial-derived risk equations are the first to predict the risk of secondary cardiovascular events in people with overweight or obesity and established cardiovascular disease but without diabetes. Incorporating these risk equations into health economic models may improve the accuracy of economic evaluations in this population.

Strengthening the management of financial security is the fundamental basis for ensuring the financial stability of mining and metallurgical enterprises under the conditions of military instability and post-war recovery. Financial stability is considered a key characteristic of the enterprise’s financial condition, determining its ability to maintain a balance of revenues and expenditures, solvency, and continuity of financial flows. The study emphasizes that in the current crisis environment, it is necessary to distinguish between "ensuring" and "strengthening" financial stability, where the latter represents a qualitatively higher level of financial security, characterized by long-term resilience and a robust resource potential for sustainable development. The purpose of the article is to define the conceptual foundations for ensuring financial stability and financial security of Ukrainian mining and metallurgical enterprises, identifying the key indicators, factors of influence, and strategic priorities for their maintenance in the face of wartime challenges and global economic transformations. The study identifies the essential features of financial stability within the framework of financial security management, including low risk levels, balanced capital structure, and the achievement of financial equilibrium. A comprehensive classification of financial stability is proposed based on its level of expression (maximum, high, acceptable, and low) and time horizon (short-term and long-term). The research highlights that maintaining financial security during the war period requires a transition from traditional control to realtime digital monitoring of financial flows. It is established that the financial security is significantly threatened by external regulatory pressures, particularly the EU’s Carbon Border Adjustment Mechanism (CBAM), which could destabilize financial flows. To counter this, the study identifies human capital and strategic capital planning as critical factors for ensuring the continuity of production and financial reliability. The study concludes that the financial stability and security of enterprises can be achieved through a synergy of effective state regulation and internal innovative transformations. It is proved that the priority for recovery is the modification of the tax stimulation mechanism for "green" investments, which will support the stability of financial flows and enhance global competitiveness. A set of measures is proposed, including the implementation of "green" certificates and the development of a state strategy for the financial stability of the industry, aimed at achieving long-term financial safety and sustainability in the global economic environment.

Objective: Type 1 diabetes (T1D) affects around 3 million people across Europe. Despite insulin therapy, T1D can lead to diabetic ketoacidosis (DKA), microvascular and macrovascular complications, hypoglycemia, and increased mortality, placing a substantial financial burden on European health care systems. Advances in automated insulin delivery (AID) systems have shown promise in improving glycemic control. This study evaluated the affordability of AID systems compared with standard of care (multiple daily insulin [MDI] injections with intermittently scanned continuous glucose monitoring [isCGM]) by examining the budgetary impact of improved glycemic control and reduced complication rates across nine European countries. Methods: The model estimated the impact of T1D complications on health care costs over a 5-year time horizon, using a hypothetical cohort of 100 individuals with T1D. Two distinct populations were considered based on baseline glycemic control: those with HbA1c ≥8% and those with HbA1c <8%. The model simulated the annual incidence and progression of chronic complications and two acute complications. Incidence rates were driven by HbA1c levels, which varied by treatment and baseline population. Severe hypoglycemia events (SHEs) were modeled separately using treatment- and population-specific rates. A treatment-neutral price was assumed, with country-specific costs applied to complications. Results: The AID system substantially reduced complication rates compared with MDI with isCGM. Among individuals with HbA1c ≥8%, overall complications declined by 61%, including a ∼70% reduction in DKA, resulting in per-person 5-year cost savings ranging from €1595 to €2810 across the modeled countries. In those with HbA1c <8%, complications excluding SHEs fell by 26%; DKA was reduced by approximately 34%, and SHEs were eliminated, translating to per-person savings of €508 to €2819 over 5 years. Conclusion: This analysis highlights the health care budget that could be freed up through the use of AID systems, enabling decision-makers to improve glycemic control in people with T1D without increasing total expenditure.

BackgroundMobile vaccine clinics (MVCs) were widely implemented in the United States (US) during the COVID-19 vaccination rollouts to overcome access barriers for underserved populations. However, the comprehensive value of these programs has not been fully assessed. This study aimed to estimate the health and economic outcomes of an MVC program that was deployed in the state of Utah beginning on April 1, 2021 across Hispanic and non-Hispanic populations in Utah.MethodsWe conducted a cost-effectiveness analysis over 1-year time horizon, comparing the MVC program implementation with a counterfactual scenario in which the MVC program was not implemented. The COVID-19 vaccinations in these scenarios were drawn from our previous estimates of MVC effect on vaccination uptake in Utah. The COVID-19 infections, hospitalizations, and deaths were projected using a Utah-calibrated Susceptible-Infected-Recovered (SIR) model. Direct healthcare costs and program costs were estimated from a healthcare system perspective in 2021 US dollars. Analyses were stratified by Hispanic and non-Hispanic populations.ResultsIn the base-case analysis, the one-year MVC program was estimated to increase 17,458 vaccines (1.34% relative increase compared to counterfactual scenario). This intervention averted an estimated 29,107 infections (7.16% reduction), 670 hospitalizations (8.96 % reduction), and 185 deaths (8.78% reduction) compared to the counterfactual scenario without the MVC program. The positive health impacts were disproportionately greater among Hispanic population compared to non-Hispanic population. The estimated cost of the MVC program implementation was $1,362,000. This investment was estimated to save $27,021,000 in averted inpatient costs and $9,352,000 in averted outpatient costs. Overall, the MVC program was estimated to save $35,012,000, representing a cost-saving intervention.ConclusionThe one-year MVC program in Utah improved health outcomes, saved costs, and enhanced equity. These findings support the use of MVCs as an effective, efficient, and equitable public health delivery strategy for immunizations and potentially other preventative services.DisclosuresAndrew T. Pavia, MD, Antimicrobial Therapy, Inc: Royalties for Sanford Guide

BackgroundIn 2018, Denver voters approved a 0.25% sales tax to fund mental health and substance misuse needs around the city. These funds are granted to organizations providing diverse services. Several grantees provide peer navigation services to improve linkage to medications for opioid use disorder (MOUD), which are effective at reducing opioid use, thereby possibly reducing risk for serious injection-related infections (SIRIs). The value of enhanced navigation services may only be realized over time given the relapsing nature of OUD. We assessed the impact of peer navigation services on SIRIs as well as the cost effectiveness.MethodsWe used a closed cohort microsimulation model of the natural history of injection drug use to project the 10-year impact of the status quo (baseline access to services without supplemental funding for programs) to enhanced care (taxpayer-funded peer navigation services and MOUD integration). The model used city-level data from the CDC’s NHBS, published data, and grantee reports on improved linkage to MOUD. Costs were derived from literature, Centers for Medicaid and Medicare Services fee schedules, and the Medical Expenditure Panel Survey, using a modified societal perspective. Outcomes included cases of and subsequent hospitalizations for infective endocarditis (IE) and skin and soft tissue infections (SSTI), life years (LYs), costs, and incremental cost effectiveness ratios (ICERs).ResultsAmong the estimated 9,697 people who inject drugs in Denver, the status quo resulted in 1,240 cases of IE (880 hospitalizations), 14,190 severe SSTIs (12,570 hospitalizations), and 4.9 discounted LYs at a discounted cost of $272,770/person over a 10-year time horizon. Enhanced care led to 12.8% fewer cases of IE (11.4% decrease in IE-related hospitalizations), 4.2% decrease in SSTIs (8.6% increase in SSTI-related hospitalizations), a 1% increase in discounted LYs, and a 3.5% increase in discounted costs. The ICER for the enhanced care strategy was $206,000/discounted LY compared to status quo. The enhanced care strategy will cost each Denver taxpayer an additional $18/year.ConclusionThe peer navigation programs supported by Denver taxpayers that improve linkage to MOUD also improve infectious disease outcomes and life expectancy and may be cost effective.DisclosuresAll Authors: No reported disclosures

Budget Impact Analysis of Fam-Trastuzumab-Deruxtecan as a Second Line in Patients With HER2-Positive Metastatic Breast Cancer in Oman.

Estonia is planning an update of its national alcohol policies where an economic return on investment (ROI) analysis is needed to guide decisions against their monetary returns. Using mostly national data sources, the ROI analysis was based on direct healthcare costs and productivity losses due to premature mortality. The interventions compared comprised availability restrictions and taxation increases. For taxation increases, associated revenue increases to government were included. All analyses used a one-year time horizon and different sensitivity analyses. In 2023, all alcohol-attributable harms in Estonia totalled €510.00 million (1.3% of the Gross Domestic Product of Estonia) with €263.91 million direct costs and €246.08 million indirect costs. The proposed availability reductions are expected to yield a net benefit of €6.33 million, whereas a 15% increase in alcohol excise taxation could lower healthcare costs and productivity losses by €1.77 million in addition to increasing tax revenue by €32.27 million. Moreover, the interventions were estimated to lead to substantial reductions in mortality and hospitalizations. In terms of ROI, the availability interventions would result in €15 gained for each euro invested, and the taxation increase in €477 per euro invested, and without revenue in €25 per euro invested. Positive ROI was also shown in all sensitivity analyses. The proposed alcohol control policies for Estonia would not only reduce mortality and morbidity but also bring sizeable gains for each euro invested. Higher ROI for taxation increase compared to availability restrictions was mainly due to the added tax revenue.

Under the imperative of achieving dual-carbon goals, the number of distributed energy resources are gradually increasing, thereby amplifying the challenges to grid stability and power balance. Consequently, there is an urgent need to leverage the potential of source-network-load-storage for enhanced power regulation and control. This paper proposes a cloud-edge-end-based multi-time scale economical management of virtual power plant (VPP) source-network-load-storage in the context of electricity-carbon market. In the first layer, a cloud-edge scheduling approach is used to optimize the source-network-load-storage system of the VPP over a long time horizon, aiming to maximize economic benefits. In the second layer, a novel real-time pricing mechanism is employed to effectively manage and regulate the electric vehicle (EV) storage and charging stations. After obtaining the economic management parameters from the previous layer, the second layer employs a real-time scheduling approach based on end-side model predictive control (MPC), to address multi-energy supply-demand fluctuations. To achieve efficient solution, the original two-layer optimization problem is reformulated using mixed-integer linear programming (MILP). Comparative analyses have demonstrated the superior economic and practical performance of the proposed two-layer optimization approach. Simulation results indicate that the total operating cost of the system can be reduced by 2.35%, with a higher flexibility of electricity market operations.

Insulin icodec, the first once-weekly basal insulin analogue, was approved in China in 2024. Although it has demonstrated robust clinical efficacy, its budget impact remains unknown, and the long-term cost-utility within the reimbursement context needs further estimates. This study evaluated the long-term cost-utility of once-weekly insulin icodec compared with once-daily insulin degludec in China. We used the validated IHE Diabetes Cohort Model to simulate lifetime costs and health outcomes for insulin-naive Chinese patients with type 2 diabetes, based on the Chinese subgroup of the ONWARDS 3 trial. The model incorporated diabetes-related microvascular and macrovascular complications, with a 40-year time horizon and 5% annual discount rate. Costs and utilities were derived from the 2024 national reimbursement drug list, the national insulin volume-based procurement policy, and published literature, expressed in 2024 US dollars. Analyses were conducted from the Chinese healthcare system perspective. Robustness was assessed through one-way and probabilistic sensitivity analyses. A complementary budget impact analysis (BIA) estimated national-level financial implications under different reimbursement scenarios. Compared with degludec, icodec increased life expectancy by 0.025 years and yielded a gain of 0.216 quality-adjusted life-years (QALYs), while reducing costs by $1450.73. One-way sensitivity analyses showed incremental QALYs ranging from 0.065 to 0.464 and cost savings from $ 265.84 to $4166.30. Probabilistic sensitivity analysis confirmed mean gains of 0.212 QALYs and cost reductions of $1320.46. The BIA estimates estimated annual savings of $1.17 million, $2.35 million, and $2.58 million in 2025, 2026, and 2027, following the reimbursement of icodec. Within the current reimbursement context in China, once-weekly icodec is a dominant strategy compared with degludec, offering greater health benefits at a lower cost for patients with type 2 diabetes and generating potential annual savings.

Prescribed-time fully distributed optimization for time-varying costs: Zero-gradient-sum scheme.

To carry out external validation of the analysis of the budget impact of the drug fingolimod after its incorporation into the Brazilian Unified Health System, comparing the real parameters arising from its incorporation in the treatment of relapsing-remitting multiple sclerosis with the estimates presented in the incorporation report in 2017. This topic is highly pertinent and makes a valuable contribution to the sparse literature on real-world BIA validation, especially in low- and middle-income countries like Brazil, yielding crucial insights for enhancing health policy optimization. Survey of the target population validated by demand measured through the dispensing of drugs, in the Brazilian Unified Health System of patients with multiple sclerosis; validation of the unit costs of drugs through purchases made by the Logistics Department of the Ministry of Health; determination of market share within the time horizon defined based on drugs purchases; estimation of direct administration costs; and monitoring of drugs to compare estimated values with the real value. Divergences were identified between real-life data collected in relation to the study's defined population and the market share of the drug fingolimod over the studied time horizon. There was a significant increase in the fingolimod market share, with the bigger market shares being in 2019 and 2020. The budget impact presented in the incorporation report was US$ 277,431,260.28, and the validated impact was US$ 194,955,442.76. The validation process of the budget impact analysis of the incorporation of the drug fingolimod in 2017 resulted in savings of around US$ 82,4million in relation to the value proposed for incorporation.

Purpose This study is to examine how developing countries can effectively implement a human rights due diligence (HRDD) framework that meets international investment law obligations while addressing domestic socio-economic realities. This study investigates the evolution of HRDD from a soft legal framework to explicit legal obligations in investment treaties and national laws, focusing on the ASEAN experience. This paper aims to understand the determinants of success or failure of different HRDD implementation approaches and to provide evidence-based recommendations for developing countries, particularly Vietnam, facing similar challenges in balancing investment protection with human rights considerations. Design/methodology/approach This study uses a qualitative comparative approach combining doctrinal legal analysis with empirical case studies. This study examines international investment treaties, national legislation and investment dispute settlements from 2011 to 2024. Four ASEAN countries (Singapore, Thailand, Malaysia and Indonesia) were selected based on their different HRDD implementation approaches, stages of development and global value chain integration strategies. This study uses a multi-level governance framework that analyzes international legal obligations, domestic policy frameworks and corporate implementation practices. Findings HRDD has evolved from a voluntary corporate social responsibility obligation to a mandatory legal requirement in investment treaties and national legislation. ASEAN countries demonstrate diverse implementation strategies: Singapore integrates HRDD into an ESG framework; Thailand develops a comprehensive National Action Plan; Malaysia focuses on a sector-specific approach (palm oil); and Indonesia uses state-owned enterprises as an implementation model. Investment dispute resolution increasingly recognizes the need for HRDD, reflecting a shift toward balancing investor protection with human rights. Research limitations/implications This study focuses on the ASEAN region, which may limit generalizability to other developing regions with different institutional contexts. The time horizon (2011–2024) captures recent developments but may not reflect long-term implementation outcomes. The limited availability of comprehensive data on corporate HRDD practices, particularly from SMEs, limits the depth of analysis. This study mainly looks at the formal legal framework rather than the effectiveness of implementation on the ground. Practical implications This study provides actionable guidance for developing countries implementing the HRDD framework. Key recommendations include developing a step-by-step legal framework rather than a comprehensive system at once, integrating HRDD into existing regulatory mechanisms, leveraging financial regulators and stock exchanges, developing sector-specific approaches for high-risk sectors, collaborating with industry associations, using state-owned enterprises as implementation models and establishing multi-stakeholder monitoring systems. Social implications Integrating HRDD into international investment law represents a fundamental shift toward protecting vulnerable communities affected by business activities. Effective implementation can prevent human rights abuses, improve labor conditions, protect indigenous community rights and ensure environmental protection. Research demonstrates that market-based approaches can complement regulatory frameworks, potentially creating positive change even in contexts of weak domestic enforcement. Originality/value To the best of the author’s knowledge, this study provides the first systematic comparative analysis of HRDD implementation across multiple ASEAN countries within the framework of international investment law. This study develops an innovative theoretical framework that connects domestic HRDD implementation with international investment obligations, filling a significant gap in existing scholarship. This study offers new insights into how developing countries can adapt international standards to local contexts while maintaining compliance with global standards. The evidence-based recommendations are particularly valuable for Vietnam and other developing countries.

This paper investigates the turnpike properties of deterministic nonzero-sum linear-quadratic (LQ) differential games. Under certain assumptions on the Hamiltonian matrix of the nonzero-sum LQ differential game, we establish the solvability of both the coupled non-symmetric differential Riccati equation (DRE) and the algebraic Riccati equation (ARE). Moreover, we identify the convergence relationship between the DRE and ARE, which is essential for understanding the turnpike properties. Over a finite but sufficiently long time horizon, the open-loop Nash equilibrium is shown to remain exponentially close to the solution of a two-objective optimization problem for the majority of the time horizon.

Combined-modality therapy (CMT) improves survival in patients with early-stage extranodal natural killer-/T-cell lymphoma (ENKTCL) compared with radiotherapy (RT) alone. However, the effect is inadequate for low-risk patients as defined by nomogram-revised risk index (NRI). As such, it remains unclear whether the survival benefits outweigh the additional costs. A Markov model was constructed to compare CMT versus RT alone for patients with early-stage ENKTCL, according to five risk groups defined by NRI model. Transition probabilities, effectiveness, and cost data were derived from the China Lymphoma Collaborative Group cohort, while health utility data were estimated from adverse effects. Life-years, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios were calculated from the perspective of Chinese payers. Evaluations for customized countries or settings can be accomplished using a web-based tool. Over the 6-year horizon, CMT increased life-years by 5.47, 5.19, 4.82, 4.62, and 4.49 years at $517,472 US dollars (USD)/QALY, $22,871 USD/QALY, $7,865 USD/QALY, $4,598 USD/QALY, and $2,278 USD/QALY for the low-risk (NRI = 0), intermediate-low-risk (NRI = 1), intermediate-high-risk (NRI = 2), high-risk (NRI = 3), and very high-risk (NRI = 4) groups, respectively. The probabilities of cost-effectiveness at a willingness-to-pay threshold of $5,208 USD/QALY were 0.00%, 0.01%, 7.40%, 72.07%, and 99.10% for each risk group. Over the lifetime horizon, all risk groups, except for low-risk group, had a probability of over 90% of being cost-effective. Estimates were varied according to country settings, integrated through a web-based customized analysis. CMT is unlikely to be cost-effective for low-risk patients but highly likely to be cost-effective for high-risk and very high-risk patients. As for intermediate-low or intermediate-high-risk patients, the cost-effectiveness of CMT varies depending on the time horizon and willingness-to-pay threshold.

Deep brain stimulation (DBS) has proven efficacy in advanced Parkinson's disease (PD) and is the current standard of care for these patients. However, its cost-effectiveness in low- and middle-income settings has not been assessed before. This study aims to assess the cost-effectiveness of DBS compared with best medical therapy (BMT) in advanced PD from a societal perspective in Egypt. We developed a Markov model with a 15-year time horizon and annual cycles to compare DBS with BMT. The cohort was aged 55-years-old at model entry and transitioned between three states: DBS, BMT, or death. Effectiveness was measured by improvement in the Unified Parkinson's Disease Rating Scale (UPDRS) and reduction in drug doses. The main outcome was quality-adjusted life years (QALYs) mapped from the UPDRS scores. The model included medical, informal care, and indirect costs. Both costs and utilities were discounted at an annual rate of 3.5%. DBS had yielded an increase of 1.4 QALYs per patient at an additional cost of 1,159,150 Egyptian pounds (EGP)/patient ($25,566). This results in an incremental cost-effectiveness ratio (ICER) of 830,726 EGP/QALY ($18,322/QALY). Patients with DBS have lower costs for medications, hospitalizations, informal care, and productivity loss. The main cost driver in the DBS arm is the device and implantation procedure costs, which accounted for 70% of total costs. The model was most sensitive to informal care costs. DBS markedly improves the quality of life for advanced patients with PD and reduces informal care and indirect costs. However, at its current price, the ICER exceeds the Egyptian cost-effectiveness threshold.

Bipolar I disorder (BP-I) is a chronic and recurrent mental health disorder, broadly characterized by patients who alternate between the extremes of the mood spectrum: mania or hypomania; and depression. In 2015, the total estimated annual cost of BP-I in the United States reached more than $200 billion, approximately 2.5 times higher than the general population, largely driven by the increased use of acute health care services. Long-acting injectable antipsychotics such as aripiprazole were developed to significantly reduce patient burden for treatment adherence compared with oral formulations, to allow consistent dosing and improved outcomes. Previous real-world evidence studies have shown the benefits of starting aripiprazole once-monthly injection (AOM) at an early stage in patients diagnosed with schizophrenia; however, the effect of early initiation in the BP-I population remains unknown. To evaluate the impact of initiating AOM 400mg (AOM 400) in adults at an early stage (<180 days) following a diagnosis of BP-I compared with late initiation (>365 days) in a real-world setting, via a retrospective analysis using claims data from the MarketScan Medicaid database. Study outcomes included the numbers of emergency department, hospitalization, outpatient, and pharmacy visits, together with the associated costs over a 1-year time horizon. A generalized linear model was used to compare the annualized costs associated with early, intermediate, and late initiators of treatment, using late initiators as the main reference group. Among 866 patients diagnosed with BP-I (median age, 36years), 161 early initiators had significantly lower risks of emergency department visits (incidence rate ratio = 0.76; 95% CI, 0.61-0.94) and outpatient pharmacy visits (incidence rate ratio = 0.82; 95% CI, 0.73-0.93) compared with 591 late initiators. Early initiators also incurred lower pharmacy visit costs ($18,787 vs $23,503; P = 0.03) and lower medical costs ($13,898 vs $18,277; P = 0.01). Overall, early initiators incurred much lower total health care costs than late initiators during the follow-up ($31,086 vs $40,599, respectively; P < 0.001). Early initiators also incurred significantly lower total health care costs than intermediate initiators ($31,086 vs $40,892; P = 0.01). This real-world study demonstrates that early initiation of AOM 400 among patients living with BP-I may offer a significant advantage of lower health care resource utilization and associated costs when compared with late initiation.

Cost-effectiveness of adjuvant alectinib in the treatment of patients with resected stage IB-IIIA ALK-positive non-small lung cancer in France, based on the ALINA study.

Background/Objectives: Stemness has been proposed as a unifying driver of invasion, treatment resistance, and relapse in oral squamous cell carcinoma (OSCC). We synthesized two complementary evidence streams to determine whether higher stemness predicts poorer survival in OSCC: (i) computational stemness signatures derived from transcriptomic/epigenetic data and (ii) tissue cancer stem cell (CSC) immunophenotypes by immunohistochemistry (IHC). Methods: Following PRISMA 2020, we searched PubMed/MEDLINE, Embase, Scopus, and SciELO. Adults with histologically confirmed OSCC were eligible. Primary outcome was overall survival (OS); disease-specific survival (DSS) and recurrence-free survival (RFS) were secondary. Two parallel meta-analyses pooled effects within domains; random-effects restricted maximum likelihood (REML) models were applied. Results: Of 785 records, 11 studies met criteria. For computational signatures (k = 6), higher stemness was associated with poorer OS (pooled HR 2.24, 95% CI 1.61–3.12; I2 ≈ 49%). Sensitivity excluding the single unadjusted Kaplan–Meier (KM)-derived estimate yielded a similar effect (HR 2.13, 95% CI 1.56–2.89). For CSC-IHC (main analysis, k = 2), CSC-positive profiles predicted worse OS (pooled HR 2.01, 95% CI 1.42–2.84; I2 ≈ 0%); results were robust to excluding an internally inconsistent study (single-study HR 2.078). An exploratory sensitivity analysis, including a 1-year HR (different time horizon), increased heterogeneity and was not considered definitive. A functional meta-synthesis converged on epithelial–mesenchymal transition/extracellular matrix remodeling, hypoxia/glycolysis, redox/ferroptosis resistance, and ribosome/rRNA biogenesis, supporting biological plausibility across modalities. Conclusions: Across computational and IHC evidence, stemness consistently portends inferior OS in OSCC, offering a biologically anchored framework for risk stratification and testable therapeutic hypotheses.

ABSTRACT Objective The aim of the present study was to evaluate the cost-effectiveness of 20-valent pneumococcal conjugate vaccine (PCV20) compared to 13-valent pneumococcal conjugate vaccine (PCV13) and 15-valent pneumococcal conjugate vaccine (PCV15) for prevention of pneumococcal disease in the pediatric population in Greece. Methods A published decision-analytic Markov model was adapted from payer perspective, to compare PCV20 (under a 3 + 1 dosing schedule per EMA approval) with PCV13 and PCV15 (both under a 2 + 1 dosing schedule) over a 10-year time horizon. Inputs for epidemiology, serotype coverage, vaccine effectiveness, utilities, and direct medical costs (€2024) were sourced from published literature and official data. Model outcomes included number of invasive pneumococcal disease (IPD), noninvasive hospitalized pneumonia, non-hospitalized pneumonia and otitis media (OM) cases, attributable deaths, costs, quality-adjusted life-years (QALYs) for each vaccination strategy and the incremental cost-effectiveness ratios for each comparison. Scenario analyses assessed PCV20 in a 2 + 1 schedule per recent national recommendations. Results The analysis indicated that, vaccination with PCV20 compared to PCV13 and PCV15 prevents an additional 1,953 and 1,514 cases of IPD 54,956 and 42,069 noninvasive hospitalized and non-hospitalized pneumonia cases, 343,353 and 271,864 OM cases and 1,377 and 987 deaths respectively, resulting in incremental gain of 23,065 (vs PCV13) and 17,118 (vs PCV15) QALYs respectively. The lower number of pneumococcal disease cases with PCV20 compared to PCV13 and PCV15, translated to a reduction in total medical care cost of €249 M vs PCV13 and €192 M vs PCV15 over the modeled time horizon. Scenario analyses showed that PCV20 remained dominant under a 2 + 1 dosing schedule. Conclusion Vaccination with PCV20, whether in a 2 + 1 or a 3 + 1 schedule, was estimated to be a dominant vaccination strategy over PCV15 or PCV13 for the prevention of pneumococcal disease in Greek infants, as expansion of serotype coverage prevents additional morbidity and costs.

The interplay between the black hole information paradox, relativistic time dilation and the extreme gravitational environment near event horizons represents one of the most profound conceptual challenges in modern theoretical physics. While general relativity predicts the irreversible loss of information in classical black hole evaporation, quantum mechanics demands strict unitarily, giving rise to the long-standing information paradox. Simultaneously, the intense curvature of space time near a black hole induces strong gravitational time dilation, fundamentally altering causal structure, the perception of quantum processes and the evolution of matter fields. This paper presents a comprehensive theoretical investigation that unifies these phenomena within the broader search for a quantum theory of gravity. We analyze the semi-classical foundations of black hole thermodynamics, the role of Hawking radiation in information loss and the implications of near horizon time dilation on entanglement dynamics. Additionally, we examine competing resolutions to the paradox including the holographic principle surfaces, firewall proposals, fuzz-ball models and loop quantum gravity inspired discreteness. Though this synthesis, we highlight how extreme gravity serves as a natural laboratory for probing the quantum structure of space time and propose a framework in which time dilation, horizon microstates and quantum information flow are deeply interconnected. Our finding emphasize that a consistent quantum gravitational resolution of the paradox must simultaneously account for causal structure, entropy bounds and the microscopic degrees of freedom encoded in the event horizon, offering new insights into the fundamental nature of space, time and information.