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Precision medical tests play a critical role in tailoring treatment plans to individual patients and optimizing medical resource utilization. This paper establishes a quantitative model to analyze the relationship between the accuracy of a precision medical test and its cost-effectiveness. Two theoretical lower bounds on test accuracy are proposed to be required for a testing strategy to be considered cost-effective. The first bound ensures that the intervention matched to a test result remains locally optimal for the reported patient class, thereby satisfying a local efficiency criterion. The second bound ensures that the testing strategy yields a higher expected net monetary benefit for the entire population compared to no testing, satisfying a global efficiency criterion. A special case analyzing sensitivity and specificity for binary test results illustrates these thresholds intuitively. Numerical simulations support these theoretical findings. The results illustrate how accuracy requirements depend on class prevalence, treatment benefits, and test costs, and may serve as a preliminary screening criterion for further evaluation.
This review synthesized literature on patient-centered burdens and economic outcomes (PCBEOs) for three populations that may be underrepresented in the literature-military veterans, people with intellectual and developmental disabilities (IDD), and individuals living in rural areas-to better understand how PCBEOs are captured for these populations. We searched PubMed, CINAHL, EconLit, Web of Science, and APA PsycInfo (January 2015-April 2025) for U.S.-based studies of PCBEOs due to medical reasons for veterans, people with IDD, or people living in rural areas or their caregivers. We categorized PCBEOs into direct medical costs, direct non-medical costs, indirect impacts, and intangible burdens. We examined population-specific rationales for studying these outcomes reported in the studies. Of 1,549 identified records, 126 met inclusion criteria. Intangible burdens were the most frequently reported PCBEOs (n = 84, 67%), while direct medical (n = 47, 37%) and non-medical costs (n = 28, 22%) were least commonly assessed. Patterns in PCBEOs varied across populations: studies of veterans focused narrowly on intangible burdens (n = 23, 85% of veteran studies), specifically composite measures of caregiver burden (n = 17 studies, 63% of veteran studies on intangible burdens). Studies on people with IDD and rural populations more often examined multiple PCBEO categories, including indirect impacts (IDD n = 33, 58%; rural n = 22, 47%) such as unpaid caregiving time; direct medical costs (IDD n = 25, 44%; rural n = 19, 40%) such as out-of-pocket medical expenses, and direct non-medical costs (IDD n = 14, 25%; rural n = 14, 30%) such as travel costs. Across all groups, few studies assessed the full spectrum of PCBEOs. Most studies (n = 96, 76%) provided research justifications tailored to their study population, though this varied across groups-about half of veteran studies (n = 13, 48%) included justifications, compared with 84% (n = 48) for IDD and 70% (n = 33) for rural populations. The frequent reporting of intangible burdens across all populations highlights substantial emotional and psychological strains faced by these groups. Considerable variability in PCBEOs examined across populations reveals gaps in comprehensive assessment of the full range of PCBEOs that each group experienced. These findings underscore the need for systematic data collection to more fully capture the range of burdens for these populations.
Little is known about how financial influences affect medical decision-making and may challenge the primacy principle of patient welfare. First qualitative results in cancer medicine identified specific decision-making situations that can be influenced by financial considerations and characterized by the type of their financial influence. These qualitative findings provide evidence that these influences are largely shaped by reimbursement strategies. Nevertheless, questions on how reimbursement strategies affect medical decision-making, and what their normative dimension is regarding the primacy principle, remain unclear. To address the research questions, we conducted an empirical qualitative content analysis according to Kuckartz and an ethical analysis using Ives' framework of reflexive balancing following the "standards of practice in empirical bioethics research" and the "framework for empirical bioethics research projects". The empirical analysis identified six financially incentivized actions: to refrain, to reduce, to deflect, to privilege, to prioritize, and to withhold. These were linked to pre-existing definitions from the normative context: rationing, prioritization, deprioritization, and selection. The ethical analysis showed that a lack of transparency about whether reimbursement strategies implement normative priorities or merely regulate costs makes it difficult to assess their compatibility with the primacy of patient welfare. The empirical and ethical analyses demonstrate that financial influences, as embedded in reimbursement strategies, can challenge the primacy principle by shaping which options appear feasible or appropriate in practice. Greater transparency and clearer justification of the goals embedded in reimbursement systems are required to determine when such influences are ethically acceptable and how they should be governed. Not applicable, as the empirical part of this study is based on qualitative interview data and does not constitute as a clinical trial.
Given the high costs of treatment with proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) and the limited US Food and Drug Administration label for these treatments in patients with stroke due to atherosclerotic disease, it is unknown whether these agents are cost-effective for reducing recurrent stroke events. To estimate the theoretical cost-effectiveness of currently available PCSK9i for the prevention of recurrent stroke in patients with high-risk intracranial arterial stenosis. This economic evaluation was a post hoc trial-based cost-effectiveness analysis of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial from a health care sector perspective. Adult patients with stroke due to intracranial arterial stenosis were included in SAMMPRIS and randomized to aggressive medical management with or without intracranial arterial stenting. Patients from the SAMMPRIS trial with complete covariate data were included in this secondary analysis. Data were analyzed from January to December 2025. A base-case assumption of 32% relative risk reduction for stroke among PCSK9i based on its low-density lipoprotein-lowering effect. Based on trial-estimated transition probabilities, annual direct-to-consumer prices for 3 PCSK9i (alirocumab: $6600; evolocumab: $7200; and inclisiran: $7920) and estimated US-based stroke care costs in 2025 US dollars, a decision-analytic Markov cohort model was developed to estimate the cost-effectiveness of PCSK9i for reducing recurrent stroke over a 5-year time horizon, with a 7% annual drug discontinuation rate and a 3% discount rate for future costs and quality-adjusted life-year (QALYs). From 1000 Monte Carlo simulations, the probability of cost-effectiveness of 3 PCSK9i was estimated at a $120 000/QALY threshold. Sensitivity analyses evaluated at an alternative threshold ($50 000/QALY), treatment efficacy (20% to 50%), and stroke care costs (50% to 150% of base estimates). A patient perspective analysis reflecting patients' out-of-pocket costs with insurance coverage was also conducted. Of the 367 patients from the SAMMPRIS included in this study, 88 were Black (24.0%), 260 were White (70.8%), and 19 Asian, Native Hawaiian or Pacific Islander, more than 1 race, or other (5.2%), and the median (IQR) age at enrollment was 59 (52-69) years. At current direct-to-consumer prices, the probability of cost-effectiveness at a willingness-to-pay threshold of $120 000/QALY over a 5-year horizon was 58.6% (95% CI, 55.5%-61.6%) for alirocumab, 53.8% (95% CI, 50.7%-56.9%) for evolocumab, and 36.7% (95% CI, 33.8%-39.7%) for inclisiran. This theoretical framework suggests that alirocumab and evolocumab were cost-effective for preventing recurrent stroke in patients with severe intracranial atherosclerosis, with all agents cost-effective under current cost-sharing programs offered by commercial and Medicare plans.
Transcatheter aortic valve implantation (TAVI) has revolutionised the treatment of severe symptomatic aortic stenosis, providing an alternative to surgical valve aortic replacement, especially in high-risk patients. Despite its benefits, significant interregional variability in TAVI access persists within Spain. This study aimed to analyse disparities in TAVI implementation across different autonomous communities, identifying the key factors underlying this variability. We conducted a retrospective observational study using data from the Spanish National Registry of Specialized Care Activity - Minimum Basic Data Set for 2016-2023, including all TAVI performed in Spain. Additionally, a survey was distributed among specialists from 123 centres to assess the factors influencing clinical decision-making, barriers to access, and resource availability. Although the number of TAVI increased across all regions, significant differences were observed in the implantation rates (between 0.63 and 2.28 per 10 000 inhabitants). Survey responses indicated that the primary determinants for TAVI indication were medical team judgment (40.0%) and patient risk stratification (36.5%). The main barriers to expanding TAVI access included rigid patient stratification (25.6%), insufficient early detection (17.8%), and resource limitations (13.3%). Participants emphasized the need for better coordination among health care levels and establishing uniform access criteria. Although TAVI adoption has increased in Spain, significant regional disparities remain, suggesting factors beyond economics contribute to access variability. Addressing these inequalities requires enhanced coordination across different health care levels, optimized resource allocation, and refined patient selection strategies. El implante percutáneo de válvula aórtica (TAVI) ha revolucionado el tratamiento de la estenosis aórtica grave sintomática, ofreciendo una alternativa al reemplazo quirúrgico, en especial en pacientes de alto riesgo. A pesar de sus beneficios, persiste una significativa variabilidad interregional en el acceso al TAVI en España. Este estudio tuvo como objetivo analizar las disparidades en la implementación del TAVI entre las distintas comunidades autónomas, e identificar los factores determinantes de la variabilidad. Se realizó un estudio observacional retrospectivo con datos del Registro de Actividad de Atención Especializada - Conjunto Mínimo Básico de Datos para el periodo 2016-2023, abarcando todos los procedimientos de TAVI realizados en España. Además, se distribuyó una encuesta entre especialistas de 123 centros para evaluar los factores que pueden influir en la toma de decisiones clínicas, las barreras de acceso y la disponibilidad de recursos. El número de procedimientos de TAVI aumentó en todas las regiones, pero se observaron diferencias significativas en las tasas de implantación, que se situaron entre 0,63 y 2,28 por 10.000 habitantes. Las respuestas de la encuesta indicaron que los principales determinantes para la indicación de TAVI fueron el criterio del equipo médico (40,0%) y la estratificación del riesgo del paciente (36,5%). Las principales barreras para incrementar el acceso al TAVI incluyeron la estratificación rígida de los pacientes (25,6%), la detección temprana insuficiente (17,8%) y las limitaciones de recursos (13,3%). Los participantes subrayaron la necesidad de mejorar la coordinación entre los niveles asistenciales y la estandarización de los criterios de acceso. Aunque la adopción del TAVI en España ha crecido, persisten importantes disparidades regionales que no pueden explicarse únicamente por factores económicos. Para abordar estas desigualdades es necesario mejorar la coordinación entre niveles asistenciales, optimizar la asignación de recursos y perfeccionar las estrategias de selección de pacientes.
Diabetes mellitus accounts for a significant share of morbidity and mortality in ages 30-70 years worldwide. In sub-Saharan Africa, diabetes care is often suboptimal for reasons ranging from health system weaknesses to patient illiteracy and non-compliance with recommendations. This study explores the potential costs and health benefits of optimising care for uncomplicated type 2 diabetes in Lagos State, Nigeria. Longitudinal data on medical care patterns and resource use (consultations, medications, diagnostics and lifestyle counselling) over a 1-year period were collected retrospectively from 84 health facilities in Lagos. Medical resource prices were obtained from a subsample of 26 facilities. Patient care gaps were assessed by comparing actual journeys to official diabetes management guidelines. Mixed-effect regression analyses were employed to explore the impact of care elements on blood glucose control and model the potential complications averted if all patients received recommended care, with extrapolation to the entire Lagos population. Data from 642 patients with uncomplicated type 2 diabetes were analysed. A one-unit increase in consultation score (a measure of the adequacy of consultation visits) and having health insurance coverage were linked to 47-unit and 29-unit lower blood glucose levels, respectively. Optimising diabetes care requires US$3716 per patient annually, totalling US$2.1 billion statewide, with medications comprising 97% of costs. Enhanced care could reduce stroke and myocardial infarction by 2% (12 675 cases) and 4% (22 282 cases) over 7 years, respectively, at a cost of US$61 492 per complication averted. The investment required to optimise diabetes care in Lagos is currently unfeasible in the existing approaches. There is a need to explore innovative financing and delivery options, including digital value-based care interventions and cost-saving care approaches such as pooled medication procurement, while also investing in local medicines production capacity and expansion of the health insurance coverage.
Pulmonary arterial hypertension (PAH) is a rare, progressive condition associated with high per-patient treatment costs and substantial clinical burden. Interpreting cost-effectiveness evidence for rare diseases remains challenging when uniform thresholds are applied across conditions that differ markedly in prevalence and scale of healthcare production. The aim of this study was to estimate a prevalence-adjusted effective cost-effectiveness threshold for PAH and illustrate how disease prevalence and production scale influence the interpretation of cost-effectiveness evidence under a fixed health care budget. We applied a previously developed prevalence-adjusted cost-effectiveness threshold framework, referred to as a generalized dynamic prevalence (GeDP) approach, to PAH using nationally representative disease prevalence data from the Medical Expenditure Panel Survey. A flexible statistical transformation was used to accommodate the highly right skewed distribution of disease prevalence and to estimate the relationship between prevalence and effective thresholds. The analysis was anchored to an empirically estimated US health opportunity cost benchmark and applied to PAH, with comparisons to selected common and rare diseases. Illustrative scenarios examined how effective thresholds evolve under changes in disease prevalence over time. Effective cost-effectiveness thresholds increased as disease prevalence declined, reflecting production-side scale effects rather than differences in societal preferences. For PAH (prevalence ≈ 0.013%), the prevalence-adjusted effective threshold was estimated at US$582,270 per QALY (95% CI 581,319-583,163), representing more than a five-fold increase relative to the reference opportunity-cost benchmark of US$104,000 per QALY applied to highly prevalent conditions. Dynamic scenarios showed that effective cost-effectiveness thresholds decline as prevalence changes over time, with larger adjustments observed for initially rare conditions. Applying a uniform cost-effectiveness threshold across diseases implicitly assumes homogeneous production conditions and opportunity costs. Prevalence-adjusted effective thresholds derived under the GeDP framework provide a quantitative, descriptive approach for contextualizing cost-effectiveness evidence for rare diseases such as PAH without redefining societal willingness to pay or prescribing decision rules. This approach can complement existing pharmacoeconomic evaluations by improving transparency around the role of prevalence and scale in shaping opportunity costs.
Despite increasing representation of women in medicine overall, significant gender disparities persist in procedural specialties such as interventional pain medicine. Women remain underrepresented as speakers at national pain conferences and in leadership roles. Additionally, a pay gap between female and male pain physicians remains. This study aims to objectively demonstrate the above-mentioned inequities. National conference faculty were analyzed across five major pain societies (ASRA, NANS, AAPM, ASIPP, ASPN) from 2020 to 2024 annual conference agendas. Gender was assigned based on publicly available information. Leadership roles were assessed by identifying the gender of pain fellowship program directors and pain medicine department chairs. Lastly, using the Association of American Medical Colleges (AAMC) Faculty Salary Report (2021-2024), we examined the compensation gap and difference in salary growth rates between genders. Across national conferences, only 25% of speakers were female, with ASRA demonstrating the most consistent female representation. Of the pain medicine fellowship programs studied, there were 36 (32.7%) female program directors and 25 (23.8%) female department chairs. Programs led by female program directors had significantly higher proportions of female faculty (OR = 1.97, CI [1.45, 2.68], p < 0.0001). Salary data revealed that at every academic rank, women in pain medicine faculty earned less than their male counterparts. Additionally, there is a statistically significant difference between the salary growth rates of male and female associate professors between 2021 and 2024 (F = 12.25, p < 0.05). Substantial gender disparities remain in visibility at national conferences, academic leadership, and compensation in pain medicine. Female-led academic programs demonstrate more gender-diverse faculties, highlighting the importance of representation in leadership. Focused efforts are needed to promote mentorship, equitable hiring, and transparency in pay and speaking opportunities to foster a more inclusive field.
The impending patent cliff projected between 2028-2030 poses significant commercial and strategic challenges for innovative pharmaceutical and biotechnology companies. To sustain growth and maintain competitive positioning, organizations are increasingly relying on strategic mergers, acquisitions, and partnerships to replenish pipelines. However, systematic quantitative strategies and framework for asset evaluation remain limited. This review outlines how clinical pharmacology and pharmacometrics (CPP) can support asset evaluation and decision-making during the asset due diligence. First, CPP spans the entire drug development continuum, providing a quantitative framework for evaluating external assets, including pharmacological plausibility, dosing feasibility, and overall development risks. Second, Model-informed drug development (MIDD) approaches can be applied to predict human pharmacokinetics, inform dose selection, and estimate the probability of technical and regulatory success. Third, we examine the emerging role of artificial intelligence and machine learning in asset evaluation and portfolio decision-making, by discovering prognostic and predictive factors, and identifying the patient sub-group. We also introduce NewCo as an emerging drug-development and business model, where quantitative strategies may be deployed. Further, we address cognitive biases, such as confirmation bias and sunk cost fallacies that can influence acquisition outcomes. Importantly, we propose the development of a bias-aware, fit-for-purpose corporate template to integrate CPP and MIDD insights, standardize evaluation criteria, and support cross-functional decision-making during asset due diligence. Embedding quantitative and bias-mitigated CPP frameworks into due diligence workflows, can help identify high-value opportunities, de-risk development uncertainties, and accelerate delivery of innovative therapies to patients with unmet medical needs.
Epidermolysis bullosa (EB) is a rare inherited disorder characterized by skin and mucosal fragility, with severe implications for physical, psychological, and social well-being. Research on quality of life (QoL) in EB remains limited, particularly in Italy, where systematic patient-reported outcome measures are lacking. To address this gap, Fondazione REB ETS developed a patient-centered QoL questionnaire (QoL-REB) constructed directly by patients and caregivers, with support from clinicians and researchers. We conducted a cross-sectional online survey between March and April 2024, recruiting Italian EB patients and caregivers through Fondazione REB and Debra Italia mailing lists. Participants completed the QoL-REB questionnaire, which assesses seven dimensions of QoL: physical health, autonomy, emotional well-being, family dynamics, social interactions, work/school life, and care experience. Responses were rated on a 4-point scale, with overall QoL assessed on a 0-10 scale. Forty-seven individuals with EB (38 adults, 9 minors; 55% female) participated, representing multiple EB subtypes, predominantly dystrophic EB (62.4%). Mean overall QoL was rated 6/10. Pain, itching, and reduced mobility emerged as the most frequent physical challenges. Over 70% of adults reported limited autonomy in daily activities, while children experienced difficulties with walking, dressing, and sports participation. Emotional distress was common, with patients expressing concerns about future prospects, body image, and dependence on others; 43% reported a need for psychological support. Family burden was evident, with both adults and minors perceiving themselves as a strain on relatives. Social limitations, workplace and school difficulties, and dissatisfaction with healthcare services-particularly a lack of EB-specific expertise in non-reference centers-were also reported. This first Italian patient-led assessment highlights the pervasive and multidimensional burden of EB on QoL. Findings underscore the need for integrated, patient-centered care models that combine medical, psychological, and social support. The QoL-REB questionnaire provides a novel, comprehensive tool to capture the lived experience of EB and may serve as a framework for international adaptation and implementation.
Tobacco use is a major contributor to the burden of chronic obstructive pulmonary disease (COPD) and other non-communicable diseases in China. People at high risk for COPD who smoke, particularly those with pre-existing chronic conditions, often remain underserved by conventional smoking cessation programmes. Population medicine offers a promising framework for proactively identifying high-burden diseases, managing multimorbidity and prioritising interventions for vulnerable populations. This protocol describes a stratified, two-arm cluster randomised controlled trial (Population Medicine Multimorbidity Intervention in Xishui County-Smoking) being conducted in Xishui County, a rural area of Guizhou Province, China. A total of 26 townships were stratified by population size and randomly assigned in a 1:1 ratio to receive either a multicomponent intervention or usual care. Eligible participants were individuals aged 35 years or older who smoked and were at high risk for COPD as identified by the COPD Screening Questionnaire. The intervention package integrates multiple components, including a digital smoking cessation programme, digital mental health support, community-based spirometry, tailored chronic disease management, health education and a performance-linked 'pay-for-population' scheme that aligns healthcare worker reimbursement with population health outcomes. Primary outcomes are smoking amount and nicotine dependence and secondary outcomes include COPD-related health outcomes, hypertension, diabetes, health risk behaviours, quality of life, healthcare utilisation and productivity loss. Follow-up occurs at 3, 6 and 12 months. Ethical approval has been granted by the Peking Union Medical College Ethics Committee (CAMS&PUMC-IEC-2024-042). Informed consent was obtained from all participants prior to enrolment. Results will be shared through peer-reviewed publication and (inter)national conference presentations. NCT06458205.
This retrospective, longitudinal, observational study evaluated the incidence of opioid use disorder (OUD) among patients newly initiating opioids to manage acute and chronic pain in the United States. Additionally, healthcare resource utilization (HCRU) and associated costs were analyzed. Adult patients newly treated with prescription opioids were identified within the MarketScan administrative claims databases (2016-2018). Patients were classified as experiencing acute or chronic pain based on total prescription pain medication use within one year of the initial opioid prescription. Subgroups of patients with or without OUD were identified using diagnosis codes. The 1-, 2-, and 3-year incidence rates of OUD were 0.21%, 0.32%, and 0.43%, respectively, among acute pain patients and 1.11%, 1.52%, and 1.92% among chronic pain patients. Unadjusted all-cause HCRU were substantially higher among patients with OUD compared to those without OUD over the 12-month period following OUD diagnosis. The associated unadjusted total all-cause healthcare costs were 3.1-times and 2.0-times higher for those with OUD compared to those without OUD in the acute and chronic pain cohorts, respectively. The total all-cause healthcare costs for patients with OUD remained significantly higher, even after adjusting for baseline characteristics. When extrapolated nationally, estimated costs for patients managing acute or chronic pain and newly diagnosed with OUD were $3.3 billion (B) and $5.9B, respectively, totaling $9.2B. Pain medication use was identified using claims for filled prescriptions; patients' actual medication usage and use of over-the-counter medications cannot be ascertained. OUD diagnosis was based on specific ICD-10-CM diagnosis codes, potentially underestimating the true incidence and economic impact. Newly diagnosed OUD following prescription opioid use for managing acute and chronic pain imposes a substantial economic burden within the first year following OUD diagnosis. Increased use of effective non-opioid analgesics may help reduce the incidence and economic burden of OUD. Opioid medications are often prescribed to help people manage pain, but they can sometimes lead to opioid use disorder (OUD), a condition where individuals become dependent on these drugs. This study looked at how often OUD occurs in people who start taking opioids for acute (short-term) or chronic (long-term) pain in the United States, as well as the healthcare costs associated with OUD. The study found that OUD is more common in people using opioids for chronic pain compared to those using them for acute pain. Over three years, about 0.43% of acute pain patients and 1.92% of chronic pain patients developed OUD. Based on descriptive analyses, patients with OUD used more healthcare services and had significantly higher medical costs than those without OUD. For example, healthcare costs were about three times higher for acute pain patients with OUD and twice as high for chronic pain patients with OUD. Even after accounting for differences in patient characteristics between cohorts, patients with OUD incurred significantly greater healthcare costs than patients without OUD. When these findings were extrapolated to the entire US population, the total healthcare costs for patients with newly diagnosed OUD were estimated to be $9.2 billion. This study highlights the significant financial and health impact of OUD. Using effective non-opioid pain treatments may help reduce the risk of OUD and associated healthcare costs.
To assess the healthcare burden of bronchopulmonary dysplasia (BPD) among very preterm infants in China. A prospective cohort study between 2022 and 2023. Chinese Neonatal Network (CHNN) participating centres. Infants with gestational age <32 weeks admitted to CHNN neonatal intensive care units. A composite rate of BPD or mortality at 36 weeks' postmenstrual age (PMA), major comorbidities, clinical resources utilisation and outcome at discharge. BPD severity was classified by Jensen et al's criteria. Among 17 793 eligible infants, 568 (3.2%) infants died before 36 weeks' PMA, 1729 (9.7%) were discharged against medical advice before 36 weeks' PMA, 9895 (55.6%) were classified as no BPD, 2751 (15.5%) developed Grade 1 BPD, 2634 (14.8%) developed Grade 2 BPD and 216 (1.2%) developed Grade 3 BPD. Infants with BPD had significantly longer hospital stays than those without BPD (median (IQR), 67 (52-84) vs 44 (34-56) days) and incurred higher total hospitalisation charges (median (IQR), 127 (91-177) vs 73 (52-103) thousand CNY) and charge per day (median (IQR), 1975 (1638-2361) vs 1714 (1409-2048) CNY). Mortality at discharge increased with BPD severity, with rates of 0.2% (18/9895) for infants without BPD, 0.5% (15/2751) for Grade 1 BPD, 2.1% (56/2634) for Grade 2 and 26.9% (58/216) for Grade 3. Similarly, the rates of major comorbidities and the need for home oxygen therapy increased with BPD severity. Greater BPD severity was associated with increased comorbidities, higher in-hospital mortality and greater utilisation of healthcare resources. These findings emphasised the ongoing need to develop cost-saving strategies to reduce the risk and severity of BPD in this vulnerable population and improve overall care.
As immunotherapy becomes entrenched in the frontline management of advanced NSCLC, post-progression treatment decisions face increasing uncertainty. A recent JAMA Network Open study using Flatiron Health data suggested that rechallenging with pembrolizumab may offer survival benefit after chemo immunotherapy progression. However, these findings raise fundamental questions about how real-world data (RWD) should be interpreted and operationalized in health economics. In this Viewpoint, we critically analyze the methodological and interpretive assumptions behind retrospective RWD-based cost-effectiveness modeling. We argue that unadjusted survival metrics absent stratification for PD-L1 status, tumor burden, or clinical performance may artificially elevate ICER/QALY estimates and misguide reimbursement decisions. Using the Velcheti et al. study as a case anchor, we highlight how structural biases in RWD can lead to premature or inflated conclusions about the value of immunotherapy rechallenge. We also propose a visual framework to distinguish between plausible clinical signals and policy-grade evidence. Health systems and stakeholders must apply greater rigor when translating RWD into economic models. We advocate for analytic transparency, pre-registered sensitivity analyses, and adjustment for patient-level variables before using RWD to inform value-based oncology. Real-world data are powerful hypothesis generators, not substitutes for controlled evidence. Without methodological discipline, their policy application risks becoming speculative rather than strategic.
Cell lines are invaluable tools for biomedical and evolutionary studies, but their genomic stability over time is often assumed rather than systematically assessed. In this study, we investigate the dynamics of genomic instability and structural rearrangements across multiple batches of a Nomascus siki cell line using a combination of single-cell template strand sequencing (Strand-seq), whole-genome sequencing (WGS), and fluorescence in situ hybridization (FISH). We identify 22 shared inversions in all the Strand-sequenced batches, confirming a common clonal origin. However, we detect additional large-scale rearrangements in all the batches, including trisomy of Chromosome 14 and the formation of isochromosomes of the same chromosome (iso-q and iso-p), leading to the rise of distinct subclonal populations. These rearrangements show evidence of clonal expansion, suggesting a proliferative advantage under in vitro conditions. From an evolutionary perspective, the gibbon genome is known for its exceptional level of chromosomal reshuffling, and this inherent plasticity may have contributed to the cell line's sensitivity to culture-induced structural changes. Despite extensive structural variation, the cell line remains stable at the nucleotide level, with ∼99% of SNPs shared across all batches. Our results illustrate how cell culture can recapitulate aspects of karyotypic evolution and underscore the need for regular genomic surveillance, particularly in long-term cultures. Furthermore, this study demonstrates the power of combining Strand-seq and cytogenetic approaches to detect both balanced and unbalanced rearrangements, especially those present in subclonal populations that would be missed by standard WGS.
Venovenous extracorporeal membrane oxygenation (VV-ECMO) is a mechanical life support modality used in patients with severe respiratory failure. Despite rising case numbers worldwide, costs are substantial, while patient-centered outcomes, particularly survival and quality-adjusted life years (QALYs), remain uncertain. High complication and mortality rates also persist. Limited financial budgets, human resources, and treatment capacities in healthcare systems require critical evaluation of whether continued use of this resource-intensive intervention at the current scale is sustainable and ethically justifiable. This study aims to provide further insight into this issue and to support healthcare decision-making by offering a structured economic and ethical framework for evaluating VV-ECMO, particularly regarding resource allocation, proportionality of costs, and the justification of its use in high-cost intensive care. This mixed-methods study consists of two parts. Part A includes two systematic literature reviews. The first examines total and daily in-hospital costs per patient, as well as outcomes measured in QALYs for adult patients supported with VV-ECMO across multiple countries between 2005 and 2024. The second aim is to identify established interventions with confirmed QALY gain that can subsequently be used as comparators for VV-ECMO. Part B evaluates the results according to the principles of medical ethics: beneficence, non-maleficence, autonomy, and justice. Given limited financial, personnel, and treatment capacities in healthcare systems, the question of how highly resource-intensive interventions such as VV-ECMO can be justified has increasing clinical, economic, and ethical relevance. By linking cost-related outcomes with a structured ethical evaluation, this study aims to contribute to a more differentiated discussion of whether and under which conditions VV-ECMO may be considered proportionate and justifiable within resource-constrained healthcare settings. Expected challenges include data availability and quality, differences in reported charges versus costs, and variation in healthcare systems, reimbursement structures, and national decision-making frameworks. These factors represent inherent limitations of international comparisons. The analysis is therefore intended as a comparative and contextual assessment rather than a formal cost-effectiveness evaluation within a single national reimbursement framework, particularly as no officially established uniform willingness-to-pay threshold per QALY exists in Germany. Not applicable. This study does not involve interventional clinical research. The protocol was registered on the Open Science Framework ( https://osf.io/24ky5 ).
Date fruits (Phoenix dactilyfera L.) are widely produced with huge wasted by-products (seeds/pits and fibers) in remarkable nutritional and economic potential value. This study aims to examine the impact of the functional properties of date seeds on health status and gut microbiota (GM) modulation in diabetic rats. Collected samples were dried and used in powdered form (DSP) for chemical compositions. Diabetic rats were then fed with this (5%, 10%, and 15%) versus control healthy group. Blood samples were used for glucose (BG) with lipid profiles (cholesterol; CHO), triglycerides (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL). Additionally, kidney (Urea, Criatinine) and histological function and GM were measured. Data indicated that DSP contain crude fiber, total sugar, and crude fat about 77%, 6%, and 6% respectively. Additionally, potassium was the highest while phosphorus shows the lowest (31.53 ± 1.19 vs. 2.48 ± 0.31 g/100 g DSP). Iron, calcium, sodium, and magnesium were 14.29 ± 0.59, 12.53 ± 0.49, 9.23 ± 0.22, and 7.60 ± 0.42 g/100 g DSP respectively. The 10% and 15% DSP supplementations affected the GM; Clostridium histolyticum reductions versus Bifidobacteria, Lactobacillus enhancement. Also, kidney functions and lipid profile improved especially at 15% supplementations (CHO and TG decrease vs. HDL-c increase). Valorization of date seed by-products indicates their potential health effects on lipids and kidney functions among diabetic models influenced by their antioxidant, mineral and fiber levels in association to GM composition. However, further studies are needed on humans with sustainable utilization manner of food waste.
Human immunoglobulins are the standard of care for patients with immunodeficiencies and represent a first-line treatment for chronic inflammatory demyelinating polyneuropathy (CIDP). This study aimed to evaluate costs associated with facilitated subcutaneous (fSCIG), conventional subcutaneous (cSCIG), and intravenous (IVIG) administration of immunoglobulin in patients with primary or secondary immunodeficiency (PID and SID, respectively) and in patients with CIDP in Italy. A cost-minimization analysis from a societal perspective was developed, considering a one-year follow-up. Direct costs included acquisition and administration costs, while indirect costs were evaluated considering productivity loss due to in-hospital IVIG using a Human Capital Approach. The posology considered for immunodeficiency disorders and CIDP was obtained from observational studies and clinical trials, respectively. Subcutaneous and intravenous administration costs were obtained from published literature. Scenario analyses were conducted to test the key assumptions of the model. This study indicates a potential reduction of annual societal expenditure in Italy of approximately €2,145 and €1,605 with fSCIG treatment in PID patients compared to cSCIG and IVIG, respectively. In SID patients, fSCIG would result in a reduction of societal expenditure of approximately €2,145 and €2,071 compared to cSCIG and IVIG. For CIDP patients, fSCIG treatment would result in a reduction of societal expenditure of €8,060 and €15,873 compared to cSCIG and IVIG, respectively. The use of fSCIG for patients with PIDs, SIDs or CIDP could lead to a reduction in the direct and indirect costs associated with the treatment of patients.
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This study aims to evaluate the cost-effectiveness of latent tuberculosis infection (LTBI) screening strategies using interferon-gamma release assays (IGRAs) among migrants, integrating social vulnerability and access barriers into the modelling framework to support more inclusive public health policy. A Markov state-transition model was constructed from a public healthcare payer perspective over a lifetime horizon. Japan. A hypothetical cohort of asymptomatic 30-year-old immigrants originating from six high-incidence countries. Screening strategies included IGRA-based LTBI testing paired with various preventive treatment regimens: 3-month once-weekly isoniazid plus rifapentine (3HP) under directly observed therapy (DOT), 3HP under self-administered therapy, 1-month daily isoniazid plus rifapentine (1HP) under DOT, 4-month daily self-administered rifampin (4R), 3-month daily self-administered isoniazid plus rifampin, 6-month daily self-administered isoniazid, 9-month daily self-administered isoniazid, pre-entry chest X-ray, postentry chest X-ray, postentry artificial intelligence (AI)-assisted chest X-ray and no screening. Costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), TB cases and TB-related deaths. Among all evaluated strategies, IGRA with 3HP under DOT was the most cost-effective strategy (US$200.1; 25.1042 QALYs; ICER vs 4R: US$29 182 per QALY gained). The current pre-entry chest X-ray remained the least costly option as screening expenses are borne by applicants. Cost-effectiveness was strongly influenced by screening access and the risk of TB reactivation. At a willingness-to-pay threshold of US$50 000 per QALY gained, IGRA with 3HP under DOT, AI-assisted chest X-ray and IGRA with 4R showed probabilities of cost-effectiveness of 40.0%, 27.4% and 22.9%, respectively. For 122 454 immigrants entering Japan in 2023, IGRA with 3HP under DOT was projected to prevent 1403 TB cases and 479 TB-related deaths. IGRA with 3HP under DOT provides strong cost-effectiveness and preventive impact. IGRA with 1HP under DOT also shows promising potential, contingent on rifapentine pricing and strengthened public health support. Integrating LTBI screening with improved access to screening and healthier living environments may reduce TB reactivation among migrants and promote more equitable health outcomes, particularly for socially vulnerable groups.