Blindness and low vision in children remain significant public health concerns, particularly in low- and middle-income countries. These conditions are often underdiagnosed and undertreated due to limited access to specialized services, spectacles, and assistive devices, posing critical challenges to health equity. The Childhood Blindness and Low Vision Programme (CBLVP) in Northern Malawi, Africa aimed to address these gaps through capacity building, advocacy, improved access to regular eye health and low vision assessments, and the provision of spectacles and low vision devices. This article reports on the activities and outcomes of the CBLVP, implemented between 2022 and 2024. Activities included establishing clinical services at a government referral eye hospital, conducting outreach screenings and assessments, and building capacity through training and mentorship. Advocacy efforts engaged stakeholders-including government officers, parents, teachers, and disability organizations, to promote awareness, increase service uptake, and provide basic skills for supporting children's use of vision at school and home. Programme monitoring drew on routine service records and feedback from stakeholders and beneficiaries, capturing key achievements and identifying challenges to inform future service improvement. A total of 2,054 children were served; among these, 370 (18%) received glasses, 70 (3.4%) received low vision services, and 96 (4.7%) underwent cataract surgery. Spectacles and low vision devices were reported to improve children's visual status, enabling better educational and vocational performance. Awareness campaigns, including radio and social events, increased visibility and service uptake, particularly among persons with albinism. Stakeholders highlighted that the absence of a regular screening and admission policy led to some children with low vision being misclassified and placed in Braille-based programs, despite being capable of learning through print. The programme demonstrated that children's vision services can be comprehensively integrated through school screening and hospital-based services. To improve service delivery, future initiatives should emphasize early identification and ensure that all children with suspected visual impairment are screened before placement in mainstream or special education settings.
The prevalence of dental and oral diseases is increasing globally, yet the utilization of dental services has not shown a corresponding rise. Cost remains a major barrier, as dental care ranks among the four most expensive health services globally. These costs are shaped by each country's health payment system, which plays a critical role in determining access to healthcare. This scoping review aims to map the existing evidence on oral health payment systems and examine how these systems influence access, utilization, equity, and financial protection in different settings. A scoping review was conducted of articles published between 2018 and 2025 that examined payment systems for oral health services. Literature searches were performed using PubMed, Google Scholar, and ScienceDirect. Eleven eligible articles revealed two main types of payment systems: insurance-based and non-insurance-based systems. Insurance models included capitation, global budgets, and reimbursement schemes, whereas non-insurance models relied on out-of-pocket or fee-for-service (FFS) payments. The FFS approach, commonly used in countries such as Saudi Arabia, the Netherlands, and Cameroon, imposed significant financial strain on patients. Insurance systems combining public and private schemes were implemented in multiple countries, including the United States, Saudi Arabia, Denmark, the United Kingdom, Hungary, Ireland, Italy, the Netherlands, Scotland, Spain, France, Germany, Romania, and Indonesia. Service coverage varied by country; for instance, government insurance in the Netherlands excluded dental care. Capitation for preventive services has been implemented in Sweden, Australia, and Indonesia. Cameroon did not have a national health insurance system (NHI). Moreover, the Netherlands and Spain had NHIs that did not cover dental health services. No single dental health financing model is universally applicable, as its effectiveness depends on government policies and local contexts. Payment systems should be designed to increase access and alleviate the financial burdens of low-income populations.
The accelerating global economic competition and the rapid development of intelligent technologies present both new opportunities and challenges for enterprises. Intelligent transformation has become an imperative trend for enhancing competitiveness, yet Chinese enterprises are still in the preliminary stages. Focusing on the supply-side (intelligent server providers) and the demand-side (adopting enterprises), this study develops a two-layer heterogeneous complex network model grounded in complex network and evolutionary game theories. We analyze the dynamic evolutionary mechanisms and key influencing factors of strategic choices for both types of firms under different scenarios. Python-based simulations reveal that increased government subsidies, reduced intelligent server costs, higher additional benefits from transformation, and appropriate pricing strategies all promote evolutionary cooperation between the two sides. Furthermore, the network structure significantly impacts strategic selection. The model's parameters are calibrated using 2023 financial data from Foxconn Industrial Internet Co., Ltd. to anchor the simulation in a representative large-enterprise scenario. This research extends the study of intelligent transformation from a static perspective to a dynamic, spatial-relationship-aware view, and addresses the limitation of participant homogeneity by employing a two-layer heterogeneous network model, thereby providing theoretical support and context-specific insights for enterprise intelligent transformation.
Aims Supervised toothbrushing programmes (STPs) reduce oral health inequalities and are a cost-effective way of preventing dental caries in children. This study aimed to detail current STP provision across England, compare it with 2022 and 2024 data, and explore barriers and facilitators to implementation.Methods A national survey of local authorities (LAs) was combined with a longitudinal multi-site case study. Survey data were analysed descriptively, while semi-structured interviews with 14 stakeholders engaged in the commissioning and delivery of STPs across four sites were thematically analysed using implementation science frameworks.Results Responses were received from 152 of 153 LAs, with 81% reporting a STP in 2025 (up from 48% in 2022 and 59% in 2024). The number of participating children more than doubled from 106,273 in 2022 to 238,636 in 2025. Case study findings highlighted two persistent barriers: uncertain funding and challenges engaging early years settings; and two key facilitators: relationship building and knowledge sharing.Conclusions STP provision is expanding but remains variable. To achieve government targets of reaching 600,000 children, attention must move beyond one-off funding to ensure recurrent investment, workforce stability, and logistical support. Building local partnerships and facilitating knowledge exchange will be critical to sustaining equitable implementation.
Mpox, caused by monkeypox virus (MPXV), has gained global attention following several international outbreaks. Accurate and high-throughput detection of MPXV-specific antibodies is essential for surveillance programmes, diagnosis, and vaccine trials. We therefore evaluated the long-term accuracy of an mpox multiplex immunoassay that measures IgG responses to 11 orthopoxvirus antigens. The assay was validated in a diagnostic accuracy study involving a Belgian cohort of clade IIb MPXV-infected individuals (n=211) and modified vaccinia virus Ankara-Bavarian Nordic (MVA-BN) vaccine recipients (n=202), who were followed up for 2 years after exposure. We used receiver operating characteristic analysis to assess diagnostic performance at multiple timepoints after infection or vaccination compared with negative controls (n=287). To explore the assay's broader utility, we also investigated correlations between antigen-specific IgG responses and neutralising antibody titres. In individuals without previous smallpox vaccination (n=149), the assay accurately detected mpox infection up to 2 years after infection, achieving 92% sensitivity (95% CI 89-97) at 95% specificity (91-98) when multiple antigens were combined. By contrast, diagnostic performance was low in previously vaccinated individuals (n=62), with sensitivities of most antigens dropping below 60% (38-77) after 6 months. Most antigen-specific IgG responses correlated strongly with neutralising antibody titres. The assay shows high sensitivity and specificity for detecting previous mpox infection in unvaccinated individuals, with reliable performance up to 2 years after infection. Strong concordance with neutralising antibody titres supports the assay's potential for monitoring long-term infection and vaccine-induced immunity. However, previous vaccination status should be considered when interpreting results. Research Foundation-Flanders (FWO), Department of Work, Economy, Science, Innovation and Social Economy of the Flemish Government (WEWIS), and Netherlands Organisation for Health Research and Development (ZonMw).
Government-led repurposing programmes are reshaping the division of labour in pharmaceutical innovation. A new power drafted into the European Union pharmaceutical reform package will allow the European Medicines Agency (EMA) to add new therapeutic indications to marketed medicines without the marketing authorization holder's consent. Companies oppose this power, but in weighing up enacting the power, society has a poor understanding of its potential to help patients. This study offers the first empirical assessment of the promise of the power. It analyses 198 medicines from 12 years, comparing EMA-authorized labels with those authorized by the US Food and Drug Administration and a leading reference for off-label uses. Sixty-seven per cent of the medicines have at least one additional use supported by clinical evidence, yielding 320 potential new uses. Of these, 39 per cent are for new diseases and 61 per cent for new patient cohorts, a third of the latter concerning paediatric populations. Commentators generally omit discussing repurposing for new patient cohorts, even though it is a focus of the European Commission. The study's results suggest that the power could be used to authorize a meaningful number of evidence-based uses, especially those already authorized in the USA, while also revealing a policy synergy for neglected populations.
Healthcare-seeking behavior is a key factor in how well a health system performs and how fair it is. In Saudi Arabia, public healthcare services are free, yet many people still choose private healthcare, especially in cities like Riyadh. It is important to understand why people seek care from private clinics to help shape health policies, distribute resources better, and improve services across the healthcare system. This study aimed to examine the frequency of private healthcare use, defined as the reported usual or concurrent use of private healthcare services, and to identify sociodemographic, behavioral, and health-related factors associated with this choice among adults in Riyadh, Saudi Arabia. A cross-sectional study was carried out in Riyadh from March to July 2023 using a multistage cluster sampling method. We randomly selected 48 government primary healthcare centers and invited adults aged 18 and older who visited these centers to participate. We collected data electronically with a validated questionnaire that covered sociodemographic details, patterns of healthcare use, reasons for choosing private healthcare, behavioral risk factors, and existing health conditions. We used multivariate logistic regression analysis to find independent predictors of private healthcare use, reporting adjusted odds ratios (AORs) and 95% confidence intervals (CIs). Of 14,239 participants, 72.4% reported using private healthcare services either as a usual source of care or alongside public services. The multivariable analysis revealed several factors to be positively related to private healthcare utilization. Those who were married were more likely to use private healthcare services (AOR 1.23, 95% CI 1.11-1.36). Those with insurance coverage were threefold higher odds of private healthcare use (AOR 3.51, 95% CI 3.13-3.94). Smokers were more likely to seek private healthcare (AOR 1.60, 95% CI 1.45-1.77) than non-smokers, and those who exercised reported increased utilization (AOR 1.83, 95% CI 1.67-2.00). Obesity was also positively related to private healthcare utilization (AOR 1.38, 95% CI 1.12-1.71), and those with heart disease had substantially higher odds of using private healthcare services (AOR 2.09, 95% CI 1.59-2.76). Private healthcare use in Riyadh is common and associated with insurance coverage, marital status, behavioral factors, and certain chronic conditions. These findings provide descriptive insights into factors related to private healthcare utilization among public PHC attendees in Riyadh, without implying causal effects or policy recommendations beyond the scope of the data.
Public Health Emergency Workforce (PHEW) plays a significant role in the detection and rapid response to emerging diseases, thus helping countries manage global threats. In line with the International Health Regulations' call for strengthening national capacities, field epidemiology training programs (FETPs) and rapid response teams (RRTs) have been developed to enhance countries' preparedness and response capacities. This scoping review synthesizes the evidence on available FETPs and RRTs and on their effectiveness as well as the challenges they face. A scoping review was conducted using EMBASE, Ovid Medline and Scopus databases in addition to the grey literature for studies published after year 2000, in the English language. Studies were selected by two independent reviewers and data were extracted into an excel sheet. Included manuscripts were analyzed through a narrative synthesis. Four thousand one hundred ten studies were identified from the three peer-reviewed databases and six articles from the grey literature. Finally, 67 studies were included in the review comprising 47 identified through our search and 20 sourced from the references. The studies on PHEW training included FETPs encompassing those with laboratory and veterinary focus, and training on rapid response. Enhancement in learning acquired, course satisfaction, application of skills in workplace and engagements in key emergency response activities were found. However, lack of funding and a standardized curriculum were still among the most common challenges facing FETPs and RRTs. While PHEW training including FETPs and RRTs are essential for building resilience against health threats, financial challenges, lack of standardized curricula and operating procedures hinders their effectiveness. Integrating One Health and laboratory skills into FETPs are vital, as seen during the COVID-19 pandemic response. Governments should work towards increasing funding and incentivizing graduate retention. They should also collaborate with organizations such as the International Association of National Public Health Institutes (IANPHI) and the Global Field Epidemiology Partnership (GFEP) to establish standardized curricula for FETP and RRT.
IntroductionLow- and middle-income countries (LMICs) like Nigeria face rising cancer incidence and mortality, with late-stage presentation and limited resources. Only eight government-funded radiotherapy centres serve a population of 223.8 million-far below the estimated 280 radiotherapy machines required. To increase patient throughput we evaluated integration of AI auto-contouring tools to expedite treatment planning, specifically target and organ-at-risk delineation.Materials and MethodsWe performed an observational, survey-based study of radiation oncology staff at our Cancer Centre. Participants were consultant and resident oncologists and medical physicists. The survey compared time spent using AI auto-contouring versus manual contouring and collected perceptions of impact, benefits, and limitations.ResultsThirty-one staff responded: 20 (64.5%) oncologists and 11 (35.5%) medical physicists. Experience with AI varied (33% ≤ 6 months; 13% ≈2 years). Respondents reported increased confidence in planning: 11 (35%) moderate, 12 (39%) moderate-high, and 8 (26%) high. Common limitations were licence availability (20, 64.5%) and technical expertise (19, 61.3%). Most respondents (20, 65%) would recommend the tool. The principal benefit was improved workflow efficiency (25, 81%). AI-assisted planning significantly reduced planning time for most tumour sites; sites with complex anatomy showed no time benefit, reflecting the need for intensive manual correction.ConclusionDeployment of AI auto-contouring at a Nigerian cancer centre reduced planning time for most sites and improved clinician confidence, but complex anatomical regions still require detailed manual oversight and additional AI training. AI tools can increase throughput in LMIC radiotherapy services, though licensing, infrastructure, and training barriers exist and must be addressed to ensure safe implementation. Future work should include multi-centre validation, formal inter-rater reliability assessment, and prospective patient-level outcome evaluation and cost-effectiveness analyses.
Severe acute malnutrition (SAM) affects millions of children globally, and treatment coverage remains below 30% in many settings, including Ethiopia. Although the Community-Based Management of Acute Malnutrition (CMAM) program has expanded nationwide, persistent service gaps remains, partly due to insufficient evidence for accurate cost estimation and budgeting. To address this gap, this study estimated the total economic cost, including provider-side financial and caregiver costs, of treating SAM through the CMAM program in two operational areas of Action Against Hunger, Ethiopia, and identified major cost drivers. A cross-sectional cost analysis was conducted in Girawa district (Oromia Region) and Adadle district (Somali Region) in 2024 from a societal perspective, including both provider-side financial and caregiver costs. Provider-side financial costs include personnel, medical supplies, therapeutic foods, equipment, transport and storage, and training and supervision. Caregiver costs include both direct costs (transport, food, and hospitalization-related expenses) and indirect costs (lost income and coping strategies). Provider-side financial costs were extracted and estimated using the FANTA CMAM costing tool. The tool automatically generated total cost per district, and the provider-side financial cost per SAM child was calculated by dividing total annual provider-side financial expenditure by the number of SAM cases treated. Caregiver costs were collected through structured exit interviews, analyzed using Excel, and summarized as mean cost per treatment episode. The mean caregiver cost was added to the provider-side financial cost to estimate the total economic cost per SAM child. The total annual provider-side financial cost for SAM treatment was USD 386,598 in Girawa district and USD 289,433 in Adadle district. Supplies, particularly RUTF and therapeutic milk, constituted the largest cost category in Girawa (57.7%), whereas repeated SAM-specific training and supervision represented the major share in Adadle (40.9%). The average provider-side financial cost per SAM child was USD 171.1 in Girawa and USD 325.2 in Adadle. The average caregivers incurred cost per SAM episode was USD 53.55. The total economic cost per SAM child, including caregiver expenses, was USD 224.65 in Girawa and USD 378.75 in Adadle. There is substantial variation in the cost of delivering SAM treatment across districts, highlighting the importance of context-specific district-level cost analyses. SAM-specific supplies and training intensity were the primary cost drivers. The incorporation of the household economic burden highlights an important but often overlooked dimension of treatment costs. These findings provide realistic district-level unit costs that can directly guide partners and governments in estimating resource needs for annual response plans while strengthening CMAM budgeting, planning, scaling up in Ethiopia.
This article examines how medical secrecy, family silence, and nascent activism produce distinct spatial-cultural regimes that shape health outcomes, care pathways, and health inequities for intersex people in Chile. It contributes a spatial-analytic framework to medical anthropology debates on clinical secrecy, contested diagnostic nomenclature, and epistemic injustice in healthcare. Multi-sited reflexive ethnography was conducted in Chile between October 2020 and December 2023, primarily in Santiago. The study draws on 30 semi-structured interviews-14 with intersex individuals (aged 19-45), of whom one additionally provided a life history interview; 5 specialist physicians, 7 parents/guardians, 2 academic researchers, 1 government official, and 1 international activist-supplemented by approximately 340 h of participant observation across virtual, institutional, domestic, and café-based settings. Analysis followed a constructivist grounded theory approach. Medical institutions, families, and activist organizations produce distinct 'geographies of secrecy' that render intersex bodies selectively visible and impose specific health consequences: clinical spaces generate epistemic injustice through information hoarding and paternalistic consent practices; family spaces enforce silence that isolates individuals from diagnosis, community, and healthcare; activist spaces offer collective recognition while simultaneously producing new exclusions. The concept of 'calibrated disclosure' captures how intersex people strategically manage visibility across spatial contexts with direct implications for healthcare access and wellbeing. The article introduces 'embodied accountability' as a methodological principle for reflexive research with small, geographically concentrated marginalized communities. Findings highlight the need for healthcare systems to address not only clinical protocols but the spatial-institutional conditions that produce epistemic injustice and impede informed consent for intersex people.
This critical review synthesizes the ethical, technical, and equity dilemmas emerging from the rapid clinical translation of liquid biopsy technologies in precision oncology. We analyze challenges across key domains, including diagnostic uncertainty and overdiagnosis, assay validation and tumour fraction estimation, artificial intelligence (AI)-driven interpretation, data governance, and equitable access. Building on this analysis, we propose conceptual frameworks to guide the responsible adoption of liquid biopsy in precision oncology. Major barriers to implementation include the technical and analytical limitations that generate false positives, false negatives, and "uninformative" results. A persistent gap between evidence and innovation means that many applications have strong prognostic validity but limited proven clinical utility. Emerging AI diagnostics also function as "black boxes," creating additional risks of algorithmic bias. Inconsistent data governance, high costs, and fragmented reimbursement policies further widen disparities in access, particularly for vulnerable populations, and undermine the potential of liquid biopsy to advance health equity. We conclude that a paradigm shift from reactive problem-solving to proactive, multi-stakeholder governance is essential. Using two linked frameworks, the Ethico-Clinical Cascade and the Pillars of Trust, we outline how technological innovation should be aligned with robust ethical oversight, transparent communication, and equity-focused policies so that liquid biopsy reduces, rather than reinforces, the global cancer burden.
Early identification and initiation of therapy for life-threatening hemorrhage is essential to minimize patient morbidity and mortality. In primary hemostasis, platelet function is integral to reach this goal, but major hemorrhage leads to impaired platelet mechanical activation and aggregation. Current devices for measuring platelet function are cumbersome or not promptly available for clinical decision making in this setting. Within this manuscript we prospectively evaluate a novel, rapid assay utilizing measures of platelet aggregation to predict hemorrhage. In this prospective cohort study at an academic regional Level I trauma center, we included adult (> 16 years old) participants who were triaged as level I or II trauma activations. The primary exposure studied was platelet aggregation analyzed on a prototype device. The primary and secondary outcomes measured were life-threatening hemorrhage (death from hemorrhage or need for hemorrhage control procedure) and transfusion requirements of > 2 units of blood components, respectively. Standard descriptive statistics were used to characterize the cohort. Predictive outcomes were analyzed using multivariable regression to compare: (1) the platelet aggregation assay; (2) clinical parameters (systolic blood pressure, heart rate, and injury mechanism); and (3) a combined model. Of 761 patients, 482 patients met inclusion criteria for our study, 36 (7.5%) had life-threatening hemorrhage and 43 (8.9%) patients required > 2 units of blood transfusion. For life-threatening hemorrhage, platelet aggregation had an area under the curve (AUC): 0.61 (95% confidence interval [CI] 0.53-0.69); clinical parameters AUC: 0.83 (CI 0.75-0.91); and the combined model AUC: 0.85 (CI 0.79-0.92) which was not significantly improved when compared to clinical parameters alone (p = 0.32). For transfusion of > 2 units, the platelet aggregation model had AUC: 0.68 (CI 0.61-0.76); clinical parameters AUC: 0.84 (CI 0.79-0.90); and combined model AUC: 0.88 (CI 0.83-0.93), improving transfusion prediction over clinical parameters alone (p = 0.013). In a cohort of traumatically injured patients, a novel, rapid measure of platelet aggregation enhanced well-established clinical parameters to predict the need for blood transfusion but not life-threatening hemorrhage. Future work should validate the clinical utility of this technology in a larger cohort and patients with significant non-traumatic hemorrhage.
Nationally representative data are essential for understanding the causes, consequences, and costs of dementia and mild cognitive impairment (MCI) and for informing policy and care planning. This study aimed to describe methodological considerations in applying the Health and Retirement Study Harmonised Cognitive Assessment Protocol (HRS-HCAP) cognitive domain structure and diagnostic algorithm to the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA-HCAP), and to generate harmonised estimates of the prevalence of dementia and mild cognitive impairment (MCI) in a nationally representative sample. A total of 1,037 participants aged ≥ 65 years completed NICOLA-HCAP. Five cognitive domains were identified, all loading onto a second-order general cognitive performance factor: orientation (0.903), memory (0.855), executive function (0.893), language-fluency (0.962), and visuospatial ability (0.812). Model fit was acceptable (SRMR = 0.065; RMSEA = 0.047; CFI = 0.916; TLI = 0.906). Following classification, 6.2% of participants were classified with dementia and 15.8% as MCI. Methodological modifications addressed software differences, normative sample derivation, and cohort-specific adjustments. These findings provide preliminary support for HCAP as a framework for producing harmonised estimates of cognitive status. NICOLA-HCAP will facilitate future investigation of modifiable risk factors for dementia in community-dwelling older adults. Validation studies are required to determine whether resulting classifications are fit for purpose.
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The increasing detection of trace organic micropollutants (OMPs) in water is intensifying the need for efficient and sustainable treatment. Ultraviolet-based advanced oxidation processes (UV-AOPs) have emerged as an important class of options for OMP control, but diversification of UV sources and wavelengths complicates selection. This review integrates mechanistic insights and performance metrics to guide UV-AOP design and source selection. Krypton-chloride excilamps emitting at 222 nm represent an emerging far-UVC source with growing research interest, but are constrained by low wall-plug efficiency and short lifetimes. Low-pressure mercury lamps remain a robust choice for large-scale applications, whereas ultraviolet light-emitting diodes offer flexible wavelength combinations and modularity but still suffer from limited wall-plug efficiency. Shorter wavelengths enhance direct photolysis and radical formation in peroxide-based systems, while activation of free chlorine is favored at 265-300 nm and chlorine dioxide responds most strongly in the UVA. In real waters, dissolved organic matter, nitrate, halides, and carbonate alkalinity redistribute photons and reshape reactive species pathways, often attenuating gains observed in clean matrices. Faster degradation does not necessarily translate into lower electrical energy per order. No single type of UV source is universally optimal; implementation should be application driven, matching wavelength-oxidant combinations to matrix conditions while balancing performance and energy efficiency across diverse treatment contexts.
Porcine reproductive and respiratory syndrome virus (PRRSV) modulates host immune responses, including apoptotic pathways, during infection. This study examined the role of TNF-α and IL-10 in regulating apoptosis during PRRSV-1 infection of bone marrow-derived dendritic cells (BMDCs), using four isolates with distinct cytokine profiles: 3262 (TNF-α+/IL-10+), 3249 (TNF-α+/IL-10-), 2988 (TNF-α-/IL-10+), and 3267 (TNF-α-/IL-10-). Early after infection (≤ 24 hpi), infected cells were predominantly non-apoptotic; by 48 hpi, apoptotic bystander cells increased markedly, consistent with a bystander apoptotic process. Neutralizing TNF-α in TNF-α-inducing isolates (3262, 3249) increased the proportion of infected cells and reduced bystander apoptosis, suggesting an antiviral role for TNF-α at the cellular level. In contrast, IL-10 blockade in IL-10-inducing isolates (3262, 2988) increased non-apoptotic infected cells without altering overall infection frequency, suggesting IL-10 modulates apoptotic progression in infected cells. Collectively, these data indicate that TNF-α and IL-10 differentially modulate apoptotic outcomes during PRRSV-1 infection in an isolate-dependent manner.
Thrombospondin-1 (TSP-1) is a matricellular glycoprotein involved in the regulation of angiogenesis, immune responses, and extracellular matrix remodeling within the tumor microenvironment. Its overexpression and interaction with receptor CD47 have been associated with tumor progression and resistance to therapy. In contrast to CD47/SIRPα blockade, which is constrained by hematological and immunotoxic adverse effects, selective inhibition of the TSP-1/CD47 interaction axis may represent a mechanistically distinct and potentially safer therapeutic approach. TAX2, a 12-amino-acid cyclic peptide, was designed as an orthosteric antagonist of this interaction. Its non-clinical profile was characterized through cross-species binding assays, receptor selectivity profiling, pharmacokinetic and biodistribution analyses in rodents and dogs, in vitro off-target and cytokine release assays, and GLP-compliant toxicology studies. Human pharmacokinetics were predicted using multiple species allometric scaling. TAX2 demonstrated binding to TSP-1 from human, rodent, and canine origin, without measurable interference with CD47/SIRPα signaling under the conditions tested. The peptide exhibited rapid plasma clearance (1-4 h), dose-proportional exposure, and detectable signal in TSP-1-rich tissues and tumor-associated regions in biodistribution studies. No relevant off-target activity or unexpected immunostimulatory effects were observed. TAX2 was well tolerated at doses up to 400 mg/kg in rats and 100 mg/kg in dogs, with no hematological or systemic toxicity, and exposures exceeding the projected clinical range. Overall, these findings establish a translational non-clinical framework for TAX2 as a first-in-class TSP-1/CD47 antagonist with cross-species-reactivity and a favorable pharmacokinetic and safety profile2.
Duchenne muscular dystrophy (DMD) is a severe X-linked disorder marked by progressive muscle degeneration and regeneration, inflammation and fibrosis. Cellular senescence has emerged as a potential driver of chronic muscle damage, yet its temporal dynamics and therapeutic relevance remain unclear. We analyzed senescent cell burden in skeletal and cardiac muscles of the DBA/2-mdx mouse model, which closely mimics features of human DMD. The senolytic combination of dasatinib and quercetin (D + Q) was administered during early or late disease phases to evaluate the impact of senescent cell clearance. Skeletal muscle strength was measured by grip strength and ex vivo force assays, while cardiac function was assessed by echocardiography. Fibrosis and senescence markers were quantified histologically, and transcriptional changes associated with senolysis were identified using bulk RNA sequencing (RNA-seq). In skeletal muscle, senescent cells appear and peak during early stages of disease progression (3-5 months), coinciding with high degeneration and regeneration activity, and then decline with age as fibrosis increases. In contrast, in the heart, senescent cells emerge at late stages of disease progression (around 12 months), correlating with heart fibrogenesis. Notably, senolytic intervention in the DBA/2-mdx mice promotes a regenerative and antifibrotic gene signature in both tissues. However, the timing of senolytic therapy determines its efficacy: early treatment with D + Q reduces senescent cell burden, decreases fibrosis, and improves fiber size and contractile performance in skeletal muscle, while later treatment reduces cardiac senescence and fibrosis but does not improve skeletal muscle pathology. Cellular senescence is a dynamic and targetable feature in DMD, with tissue- and age-specific patterns. It represents a potential modifiable therapeutic target, and temporally optimized senolytic strategies could serve as effective adjuncts to current and emerging DMD treatments.
Multiple myeloma (MM) is best understood as a dynamically evolving genomic ecosystem shaped by inherited susceptibility, early oncogenic events, and continuous selective pressures. We propose an evolutionary genomics framework integrating germline risk, disease initiation, clonal diversification, and therapeutic adaptation into a unified model of MM biology. Polygenic risk burden, rare predisposing variants, and alterations in DNA repair and telomere pathways create a permissive background that influences precursor states and immune interactions. Primary cytogenetic events, particularly immunoglobulin heavy chain (IgH) translocations and hyperdiploidy, establish biologically distinct founding clones and constrain subsequent evolutionary trajectories. Disease progression is driven by secondary chromosomal alterations, copy number changes, MYC activation, TP53 loss, and structural rearrangements, promoting genomic instability and transcriptional plasticity. Longitudinal studies reveal branching clonal architectures shaped by treatment-driven selection. Integrating germline and somatic landscapes within an evolution-aware precision framework may improve risk stratification, anticipate high-risk trajectories, and support adaptive strategies to achieve more durable disease control. While polygenic risk scores (PRS) provide insight into inherited susceptibility, they are not yet clinically actionable for risk stratification or screening in MM and currently remain research tools. This framework provides a clinically oriented basis for applying genomic biomarkers to risk stratification, treatment selection, and longitudinal monitoring.