Bulletin of Mathematical Biology

Background: Self-supervised learning may improve segmentation when labelled data are limited, but its benefit may depend on model and initialisation strategy. This study evaluated in-domain masked-reconstruction pretraining across limited annotation budgets. Methods: The International Skin Imaging Collaboration (ISIC) 2016 development set was partitioned into 765 images for self-supervised pretraining, 94 for fine-tuning and 41 for validation. Five nested annotation budgets (12-94 images) and five seeds were evaluated on the 379-image test set. A custom U-Net compared random and in-domain self-supervised initialisation; a ResNet-34 U-Net compared random, ImageNet, in-domain self-supervised and sequential ImageNet-to-self-supervised initialisation. Models trained with 94 labelled images were evaluated without adaptation on ISIC 2017. A separate experiment examined restoration-based pretraining. Results: In the custom U-Net, self-supervised pretraining achieved higher mean Dice than random initialisation at all five budgets, including 0.664 versus 0.615 with 12 labels and 0.811 versus 0.768 with 94 labels. Seed-level 95% confidence intervals for paired differences excluded zero at 47 and 94 labels but not at the other budgets. With 47 labels, the self-supervised model achieved mean Dice of 0.789, compared with 0.768 for random initialisation with 94 labels. In ResNet-34, ImageNet initialisation achieved higher mean Dice than in-domain self-supervised pretraining at all five budgets, and adding self-supervised pretraining after ImageNet reduced mean Dice at four of five budgets. All six 94-label configurations achieved lower mean Dice on ISIC 2017 than ISIC 2016. In the restoration experiment, mean Dice was 0.686 with random initialisation and 0.638-0.642 following pretraining. Conclusions: In-domain masked-reconstruction pretraining improved mean Dice relative to random initialisation in the custom U-Net, but not consistently in the ResNet-34 U-Net, where ImageNet initialisation performed better at every budget. Adding self-supervised pretraining after ImageNet provided no consistent gain. These findings are specific to the dermoscopic lesion-segmentation experiments and do not establish melanoma-specific diagnostic or clinical performance.

This paper examines the impact of Cancer Care Ontario's regionalization of lung cancer surgery on blood transfusion use for thoracic surgery at The Ottawa Hospital. Using aggregate data scraped from the paper ''Changing trends in blood transfusion: an analysis of 244,013 hospitalizations'' by Shehata et al. (2014) we estimated the effect regionalization on the log mean number of blood transfusions among thoracic surgeons (who treat lung cancer), utilizing other surgical specialties as controls. We found that the average number of blood transfusions increased significantly among thoracic surgeons following the opening of a new cancer care centre at the hospital in December 2009, while control specialties showed no parallel change. Contextualizing these results in a modified ''population level'' treatment threshold model, it is argued that the main driver of this increase in blood transfusions among thoracic surgeons was due to the influx of less skilled thoracic surgeons to The Ottawa Hospital, and the closing of thoracic surgery units at smaller hospitals which was part of the broader regionalization process.

The efficacy of current antiretroviral interventions for prevention of vertical HIV transmission is both a triumph and a challenge for future efficacy studies of novel agents, including long-acting antiretroviral agents. Given the effectiveness of current antiretroviral interventions, standard randomized controlled trials to assess novel interventions targeted towards further reducing vertical HIV transmission may be infeasible due to required sample sizes. To address this study design challenge, we propose a novel augmented clinical trial design, where a randomized trial with an active comparator is augmented with a concurrent observational cohort to supplement the standard-of-care arm. The proposed design and analysis can overcome sampling biases, and an associated diagnostic can evaluate potential biases from unmeasured covariates. The proposed trial design is illustrated with an example and studied further using a simulation study. In the illustrative example, an augmented trial with a 3:1 allocation ratio in the trial component yielded an unbiased treatment effect estimate, as compared to the trial component alone, and the standard error was reduced substantially. Although the total sample size of the augmented trial was larger than a similarly powered 1:1 standard trial, the sample size of the augmented trial's trial component was half the size of the standard trial and within the range of historically similar trials, thereby providing both feasibility and potential cost advantages. Although limitations with this design remain, many of these limitations can be mitigated by careful study planning and coordination. Augmented trials provide a potentially applicable solution to studying the efficacy of long-acting antiretrovirals for infant postnatal prophylaxis against HIV.

The aim of this study was to develop a framework for assessing the incremental value of decisions on drug amount, timing, input structure, cessation and restart. The LOGOS (Longitudinal Optimization of Global Outcomes and Strategies) approach combines matched nested regimen classes, mechanism-specific benchmarks and evidence requirements in a single longitudinal comparison. Thus, the contribution of additional regimen freedom is assessed separately from improvements due to different resources, constraints or evaluation horizons. Nested feasible classes have nondecreasing objective suprema, whereas a strict gain requires a feasible witness above a valid bound for the smaller class. The approach is illustrated through analytical examples of periodic smoothing, matched desensitization, relaxed exposure allocation, finite-course loading and safety after cessation. In a normalized finite Emax model, integrated benefit increased from 0.629606 for three equal boluses to 0.672945 after optimization of amounts, 0.677043 for an amount-and-time candidate and 0.679553 for a globally certified loading-maintenance-coast solution. The adjacent observed gains were 6.88%, 0.61% and 0.37%, respectively, and all schedules satisfied the full-tail injury bound. In addition, a periodic factorial example separated response curvature from a joint recovery and repair process, including a null case and results dependent on feasibility constraints. The LOGOS framework allows assessment of whether additional regimen flexibility improves benefit, provides no added value or restores feasibility. These dimensionless examples support conditional mathematical and model-based conclusions; clinical superiority and safe restart in patients have not been established.

Introduction: Lichen sclerosus (LS) is a chronic inflammatory dermatosis predominantly affecting the anogenital region of both women and men. Sexual dysfunction remains among the most debilitating and overlooked consequences of the disease, as available patient-reported outcome measures are either restricted to one sex or capture sexual health only partially. The aim of the present work is to validate the Qualisex questionnaire (in its the Italian version) in patients with LS and to evaluate its psychometric properties, factor structure, convergent, discriminant validity, and sex symmetry. Methods: A cross-sectional study was conducted on 211 patients (167 women, 44 men; mean age 52.9 years) with a confirmed diagnosis of LS. Participants completed the Italian Qualisex, Skindex-29, DASS-21, and sexual-health-specific scales, the Female Sexual Function Index (FSFI) for women, and the International Index of Erectile Function (IIEF) for men. Construct validity was assessed via Principal Component Analysis (PCA), and reliability via Cronbach's alpha. Convergent and discriminant validities were evaluated against standard psychometric batteries. Results: Item 2 was removed due to low communality (0.167). PCA on the remaining 9 items revealed a two-factor structure accounting for 72.5% of total variance: Component 1 (Sexual Functioning and Satisfaction, 59.89%) and Component 2 (Partner Devaluation, 12.66%). Internal consistency was high (alpha= 0.911 overall; alpha= 0.841 in women; alpha= 0.899 in men). Qualisex scores correlated strongly with Skindex-29 Social Functioning (r = 0.582) and Emotions (r = 0.531) subscales, as well as FSFI (r = -0.391) and IIEF (alpha= -0.566). Discriminant validity was supported by low-to-moderate correlations with DASS-21 domains (r < 0.38). While FSFI and IIEF showed significant negative correlations with age (p = 0.002), Qualisex remained age-independent across sexes (p > 0.05). Conclusion. The 9-item Italian Qualisex is a reliable, sex-symmetrical, and age-independent patient-reported outcome measure for assessing sexual health impairment in LS, successfully isolating disease-specific distress from physiological aging and general distress.

Retention in antiretroviral therapy (ART) programmes remains a major public health challenge in HIV care, with loss to follow-up (LTFU) and death threatening treatment success. Because these outcomes are competing events, conventional survival methods may yield biased estimates of their incidence and associated risk factors. To estimate the cumulative incidence of LTFU and mortality and identify factors associated with these outcomes among adults receiving ART in Northern Ghana using a competing-risks framework. We conducted a retrospective cohort study of 329 adults living with HIV who initiated ART at Nalerigu Baptist Medical Centre, Ghana, between January 2013 and December 2019. Fine--Gray subdistribution hazard models were used to evaluate predictors of LTFU and death while accounting for competing risks. Cause-specific Cox proportional hazards models were fitted as a sensitivity analysis. The incidence rates were 2.2 per 100 person-months (95% CI: 1.9--2.6) for LTFU and 0.74 per 100 person-months (95% CI: 0.57--0.98) for death. At 36 months, the cumulative incidence was 50.2% for LTFU and 16.0% for death. Patients residing closer to the clinic had a lower cumulative incidence of LTFU than those living farther away (SHR = 0.68, 95% CI: 0.49--0.93), whereas higher baseline weight was associated with increased LTFU (SHR = 1.02 per kg, 95% CI: 1.00--1.04). Mortality was lower among patients receiving efavirenz-based regimens (SHR = 0.27, 95% CI: 0.15--0.50), females (SHR = 0.39, 95% CI: 0.18--0.85), and those with higher baseline weight (SHR = 0.93 per kg, 95% CI: 0.90--0.96). Findings were broadly consistent in cause-specific Cox models. LTFU was substantially more frequent than mortality among adults receiving ART in Northern Ghana. Travel distance to the treatment facility was an important barrier to retention, while ART regimen, sex, and baseline weight were associated with mortality. Expanding access to ART services through decentralized and community-based models may improve retention and support efforts to achieve HIV control targets.

We develop an age- and immunity-structured COVID-19 model with setting-specific contacts, calibrated to Ontario incidence and hospital admissions before Omicron. We simulate counterfactual vaccination strategies and contact restrictions in schools, workplaces, and other community settings, evaluating projected severe-case demand against an illustrative healthcare-capacity benchmark. Vaccination combined with workplace and community contact restrictions keeps simulated demand within capacity. In contrast, relaxing restrictions in either setting produces large surges and repeated capacity threats, even when school restrictions remain. School-only changes produce smaller effects on severe disease. These findings highlight the value of vaccination and setting-specific contact restrictions that prioritize workplace and community settings for pathogens with adult-concentrated severe outcomes.

Since its inception in 2003, the United States President's Emergency Plan for AIDS Relief (PEPFAR) has played a central role in HIV/AIDS prevention and treatment across Sub-Saharan Africa. Following the January 2025 suspension of United States foreign aid, which includes PEPFAR funding, countries across Sub-Saharan Africa demonstrated varying governmental responses to the resulting HIV funding disruptions. This study evaluates whether national characteristics were associated with a country's ability to respond to this funding crisis. Countries in Sub-Saharan Africa receiving PEPFAR funding were classified into one of three response categories: Level 1 (minimal or no governmental response), Level 2 (government response without sufficient plans or resources to fully offset funding losses), or Level 3 (high governmental response with strategies to maintain HIV/AIDS prevention and treatment services). Response categories were compared with national Human Development Index (HDI), GDP per capita, HIV prevalence, total population living with HIV, annual HIV mortality, and historical PEPFAR funding. Univariable proportional-odds ordinal logistic regression was used to identify factors associated with response level. Five countries (17.2%) were classified as Level 1, 10 (34.5%) as Level 2, and 14 (48.3%) as Level 3. Higher HDI was significantly associated with stronger governmental response (OR = 4.05; 95% CI, 1.49-11.04; Holm-adjusted p = 0.0376). GDP per capita (OR = 2.35; 95% CI, 1.00-5.51; unadjusted p = 0.0489) and HIV prevalence (OR = 3.53; 95% CI, 1.03-12.11; unadjusted p = 0.0452) demonstrated positive associations before adjustment for multiple comparisons, but neither remained significant after Holm correction (adjusted p = 0.2261 for both). Historical PEPFAR funding, total population living with HIV, and annual HIV mortality were not significantly associated with response level after adjustment. Countries with higher levels of human development demonstrated stronger governmental responses to the 2025 PEPFAR funding disruptions. Several countries with minimal documented responses were also affected by active conflict or political instability, potentially compounding their vulnerability to treatment interruptions. These findings suggest that broader national development may play an important role in governmental responses to funding disruptions and highlight the need to strengthen resilient health systems, diversify HIV financing, and prioritize support for countries at greatest risk of future funding shocks.

The -Bonacci weighted sequence space {ell}(,) is introduced for [&ge;] 2, 1 [&le;] < {infty}, and > 0). It is proved to be a Banach space which is isometrically isomorphic to {ell}, with an unconditional Schauder basis. The space is also reflexive and uniformly convex. Its strict inclusion chain, continuous dual, and asymptotic truncation estimate of order - / are also established. Based on this framework, Scaled &#119898-BonacciNet is proposed as a lightweight CNN that rescales Fibonacci-Net channels using the dominant &#119898-Bonacci root and employs depth wise separable convolutions. Tribonacci-Net achieved 96.09% accuracy and a 0.9581 macro F1-score on the 15-class Brain MRI dataset using 0.85 million parameters and 0.366 GFLOPs. Pentanacci-Net attained 95.87% accuracy on the 44-class dataset while reducing parameters and FLOPs by 47.10% and 44.48%, respectively. On the CKD ultrasound dataset, Hexanacci-Net achieved 83.75% accuracy and a 0.7941 macro F1-score, with corresponding reductions of 50.37% and 45.10%. These findings support dominant-root scaling as a structured approach to lightweight CNN design.

Background: Lean Healthcare has been adopted as an approach to reducing waste, enhancing process efficiency, and optimizing clinical and administrative workflows. However, empirical evaluations aimed at establishing a causal relationship between Lean Healthcare interventions and outcomes remain limited. This evidence gap is particularly pronounced in the context of large-scale implementations in low- and middle-income countries, where more efficient allocation could yield substantial improvements in population health. Methods: We conducted an impact evaluation study employing a staggered difference-in-differences approach to estimate the effects of the Lean Healthcare in Emergency Departments (ED) initiative in the Brazilian context. The intervention was implemented between January 2017 and December 2025 across 309 hospitals. We analyzed hospital-level indicators of the number of hospitalizations and the average length of stay (in days) among patients admitted through urgent or emergency pathways. Results: Our estimates suggest that the intervention was associated with an average increase of 38.6 admissions per hospital per month (p = 0.033), corresponding to approximately a 5.9% increase relative to the monthly admission volume. We also observed a reduction of 0.184 days in the average length of stay (p = 0.058), equivalent to an approximately 3.0% decrease in hospitalization time. These effects exhibited distinct temporal dynamics: the effect on the number of hospitalizations emerged gradually and increased with the duration of the intervention, whereas the reduction in length of stay became evident earlier. Conclusion: This study provides evidence of a causal effect of Lean Healthcare implementation in emergency departments on operational performance. The simultaneous increase in admissions and reduction in length of stay suggests improved bed productivity and effective capacity without expanding physical infrastructure. These findings support the use of flow-management methodologies as an effective strategy for mitigating emergency department overcrowding while increasing service capacity.

Estimating the correlation between subject-specific rates of change is a common objective in longitudinal studies. A natural approach is to fit ordinary least squares regressions per subject and correlate the resulting slope estimates directly. Under complete data, this slopes-first estimator is algebraically equivalent to a contrast-based plug-in estimator derived from the joint variance-covariance matrix of the two signals across time. Under independent dropout, however, the slopes-first approach implicitly applies heterogeneous weights across missing-data patterns, introducing bias whenever the cross-covariance between the two signals is not constant over time. We formalise this result and propose an unbiased alternative that estimates the joint covariance matrix before applying the contrast. We further extend our results to include covariates as well. Simulations confirm that the slopes-first estimator is biased under non-constant cross-covariance while the proposed alternative remains unbiased. Further, we show in a real-world example that the two estimators can lead to different scientific conclusions and recommend that researchers working with longitudinal data inspect the missing data pattern to make an informed decision about the estimator of choice.

Background: Although perioperative fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) is the standard neoadjuvant regimen for resectable gastric and gastro-oesophageal junction adenocarcinoma, evidence describing treatment delivery in routine clinical practice remains limited, particularly regarding relative dose intensity (RDI) and treatment completion. Objectives: To evaluate real-world delivery of preoperative FLOT chemotherapy, including treatment completion, progression to surgery, RDI, toxicity and exploratory changes in estimated lean body mass (LBM). Methods: A retrospective single-centre service evaluation included consecutive patients receiving neoadjuvant FLOT during 2024. Outcomes included treatment completion, surgery, RDI, toxicity, pathological response and estimated LBM. Descriptive statistics were used. Results: Twelve patients were included (median age 68.6 years; 91.7% male). Eleven (91.6%) completed all four preoperative cycles and proceeded to surgery. Mean RDI was 76.7%. Pre-emptive dose capping was the predominant dose modification strategy, with only one reactive dose reduction. Two grade 3 adverse events occurred. Major pathological response (Mandard grade 1-2) was observed in 2/12 patients (16.7%). Mean estimated LBM declined from 54.3 to 53.4 kg. Greater LBM loss appeared to coincide with poorer clinical outcomes. Conclusions: High treatment completion and progression to surgery were achieved despite reduced RDI. These findings support prospective evaluation of strategies to optimise chemotherapy delivery while maintaining tolerability in routine clinical practice.

Background: The C-reactive protein-albumin-lymphocyte (CALLY) index integrates systemic inflammation, nutritional status, and immune function. We evaluated its association with survival in primary lung malignancies. Methods: Embase, PubMed, Scopus, and Web of Science were searched from inception to 18 September 2026. Risk of bias was assessed using the Quality In Prognosis Studies tool. Hazard ratios (HRs) were synthesized using random-effects models with restricted maximum likelihood estimation and Hartung-Knapp adjustment. Sensitivity analyses, subgroup analyses, and meta-regression examined robustness and heterogeneity. Results: Eleven studies contributed 13 cohorts to the overall survival (OS) analysis and 8 cohorts from seven studies to a combined recurrence/progression-free survival (RFS/PFS) analysis. Lower CALLY was associated with poorer OS (HR 1.78, 95% CI 1.49-2.12; I2=71.6%) and poorer RFS/PFS (HR 1.60, 95% CI 1.40-1.84; I2=0%). Associations persisted in leave-one-out analyses. No statistically significant subgroup differences were detected. Funnel-plot asymmetry suggested small-study effects for OS and RFS/PFS. Seven studies had moderate and four had high overall risk of bias. The certainty of evidence was rated as low for both OS and RFS/PFS, primarily due to risk of bias, heterogeneity, and endpoint indirectness. Conclusion: Lower CALLY was associated with adverse survival outcomes in the current synthesis. Methodological limitations and variation in biomarker measurement and endpoint definitions restrict interpretation. Prospective validation using standardized measurements and clinically coherent outcomes is needed to establish incremental prognostic value and clinical utility. Keywords: CALLY index; lung cancer; prognosis; overall survival; systematic review; meta-analysis

PURPOSE: Women with metastatic breast cancer (MBC) are at risk of developing financial toxicity due to prolonged treatment. Resilience has been identified as a key protective factor associated with better quality of life among cancer populations. However, it is unknown if resilience is associated with financial toxicity. We sought to examine the relationship between resilience and financial toxicity among women with MBC and explore whether socioeconomic factors moderate this association. PATIENTS AND METHODS: Our sample included 209 women with MBC who completed self-reported questionnaires of the Resilience Scale Specific to Cancer (RS-SC) and the Comprehensive Score for Financial Toxicity (COST). Participants (n=2) with missing data were excluded from analysis. We conducted multiple linear regression to examine the association of resilience with financial toxicity. Interaction terms were used to test moderating effects of age (18-39, 40-64 and > =65 years), race, education, health insurance, household income and employment status. RESULTS: Of the sample, 56.5% were aged 40-64 years, 76.6% were White, and 79.9% had a college or master degree or above. Women reported moderately high resilience with mean RS-SC score of 34.49 (SD = 6.67), and moderate financial toxicity (mean COST score =21.01 [SD = 10.51]). Adjusting for covariates, higher resilience was linked to better financial well-being (b = 0.37, SE= 0.11, 95% CI [0.14, 0.59], P < 0.01). Age, education and health insurance moderated this relationship, with resilience more strongly associated with better financial well-being among those aged 40-64 years, with college/master degree or above and private insurance. Race, household income, and employment status did not moderate the association between resilience and financial toxicity. CONCLUSION: Women with MBC who reported higher resilience are more likely to experience better financial well-being, but the strength of this association varied by socioeconomic factors. Further research is needed to confirm these findings. Our results have important implications for incorporating resilience into financial toxicity interventions and tailoring such interventions based on individual socioeconomic characteristics.

Background. Regulatory pressure to avoid confusingly similar drug names appears to have pushed manufacturers to coin more distinctive proprietary names, but no one has quantitatively analyzed this trend. Objective. To determine whether proprietary drug names became more orthographically distinctive (unusual in spelling) over time. Methods. We examined 1,321 US Food and Drug Administration (FDA) new molecular entity (NME) names (1985-2024), 2,769 FDA Orange Book trade names (1982-2026), 177,337 US pharmaceutical trademarks (1980-2026), and 1,273 generic names (1982-2025). Compared to prior names (including those already marketed) and ordinary English, we scored each name's character trigram (three-letter sequence) surprisal (statistical unexpectedness) and its edit-distance similarity to the closest existing names. Linear regression tested time trends, controlling for name length. Results. Mean NME trigram surprisal rose in every decade between the 1980s and 2020s, from 7.21 to 8.50 nats (natural-logarithm units, higher meaning less predictable), an 18% increase (b = 0.038, p < .001, R2 = 0.34). Half of 2020s names (7% in the 1980s) contained a letter sequence found in no common English word (e.g., Jesduvroq, Omvoh). Nearest-neighbor similarity fell after the early 1990s. Trademark data showed the same trend (b = 0.016, p < .001). Generic names showed a weaker trend (b = 0.011, R2 = 0.063). Conclusions. Over four decades, drug names became more orthographically distinctive, consistent with namespace crowding, deliberate efforts to avoid confusing names, and branding strategy. Because unfamiliar letter sequences can introduce other error pathways, increased distinctiveness does not necessarily imply improved safety.

Background: Cost-effectiveness analyses (CEA) built on simulation models are usually delivered through project-specific scripts. Each new model, and often each new question, rebuilds the same scaffolding: parameter management, calibration, base-case analysis, sensitivity analysis and export. This is costly, and is where traceability between an estimate and the model version producing it is lost. We present THALASSA, a web application providing this infrastructure once, for any model satisfying a small programming contract. Methods: A simulation model is connected by one file implementing a fixed contract of R functions that determine its behaviour. THALASSA exposes the complete CEA workflow in a browser: a generated overview of the connected model, parameter editing, calibration, base-case comparison with the efficiency curve, and deterministic and probabilistic sensitivity analysis at a willingness-to-pay threshold, each with timestamped file export carrying the parameter values it was run with. Every session is bound to a repository version, so results carry their generating model version. Results: We demonstrate THALASSA on two public models of contrasting difficulty: a simple tutorial model and a generic cancer screening model with two competing natural-history pathways and a 21-dimensional calibration deliberately built to be more complex. Both ran on the same unmodified setup, implementing the same contract, with no code changes. Conclusions: Separating analysis infrastructure from model logic makes the CEA workflow reusable across projects and reproducible by construction. A modelling team can move from a versioned repository to audit-ready, exportable CEA outputs without writing analysis code. The integration effort does not grow with model size and one installation serves unrelated projects.

Background and Objective: Adding belzutifan to adjuvant pembrolizumab improved disease-free survival (DFS) in LITESPARK-022, but its durability beyond the 1-year treatment is unknown. Methods: Following a registered plan, we reconstructed individual patient data from published Kaplan-Meier curves of ten phase 3 adjuvant renal cell carcinoma trials. Within each trial, we estimated restricted mean survival time differences ({Delta}RMST), hazard ratios (HRs) before and after planned treatment ended, and DFS differences. Key Findings and Limitations: In LITESPARK-022 (central review), the 24-month {Delta}RMST was 1.34 months (95% confidence interval 0.73-1.95), and the belzutifan arm remained ahead after month 12 ({Delta}RMST increment 0.74 months/yr, 0.32-1.19). The HR was 0.55 (0.43-0.71) before month 12 and 1.16 (0.87-1.54) afterwards (post/pre ratio 2.10); investigator assessment showed similar attenuation. Similar ratios occurred in KEYNOTE-564 at its first interim analysis (2.02), whose benefit persisted, and in SORCE and PROTECT (2.09, 2.59), whose benefit faded. From months 12 to 30 (post hoc), the DFS difference changed by -3.7 percentage points (-8.1 to 0.8) with central review and 0.6 (-4.0 to 5.0) with investigator assessment. Data were reconstructed, and follow-up was short. Conclusions and Clinical Implications: Relative hazard reductions with belzutifan were greater before month 12; durability of the absolute DFS advantage is uncertain and assessment-dependent, so single-HR projections should be avoided.

Introduction: HIV and childhood maltreatment (CM) are both chronic stressors that disproportionately affect women, with each contributing to accelerated biological aging. Whether biological aging markers are convergent and associate with HIV and CM is unclear. Methods: We studied 238 women (122 with HIV), characterised for CM severity, and assessed biological aging using absolute telomere length (aTL), mitochondrial DNA copy number (mtDNAcn), magnetic resonance imaging-based brain-predicted age difference (MRI-BPAD), and DNA methylation age (DNAmAge) clocks. CM was measured with the Childhood Trauma Questionnaire-Short Form total score. We examined intercorrelations among biological aging markers to assess convergence and conducted linear regression models to test moderation by HIV status and CM severity. Results: PWH had shorter aTL, lower MRI-BPAD, and higher Horvath age acceleration (HorvathAA), HannumAA, PhenoAA, and extrinsic epigenetic age acceleration (EEAA). CM had limited associations with biological aging markers. Absolute TL correlated weakly with mtDNAcn (p = 0.36), PhenoAA (p = -0.18), and EEAA (p = -0.18), while MRI-BPAD correlated weakly with PhenoAA (r = 0.20). DNAmAge clocks were moderately to strongly intercorrelated (r = 0.35 - 0.93). No robust two- or three-way moderation effects were observed after false discovery rate correction. Conclusion: Our findings support a multidimensional pattern of biological aging, with substantial convergence among epigenetic aging measures but limited relationships across different markers, largely independent of HIV status and CM severity. Longitudinal approaches are needed to clarify how distinct biological aging markers relate to one another and to health outcomes over time in vulnerable populations.

Background Immune checkpoint blockade (ICB) has become the standard of treatment for metastatic melanoma (MM). However, patients with melanoma brain metastases (MBM) are often excluded from clinical trials. Here we analyse patients within the real-world OxCITE cohort receiving ICB treatment for metastatic melanoma, with a focus on MBM, aiming to discern outcomes, prognostic factors and peripheral biomarkers. Methods Patients eligible for ICB treatment were recruited prospectively. Demographic, clinical and radiological data were collected from electronic patient records. Plasma samples were collected prior to the first cycle of treatment for plasma proteomic analysis. Results 307 patients were included, 81 of whom had MBM on commencing ICB. No difference in overall survival between patients with and without brain metastases was noted on multivariable analysis (HR=1.1, 95% CI 0.73-1.6, p=0.68), whereas hepatic metastases were associated with increased risk of death (HR 1.7, 95% CI 1.2-2.4, p=0.0019). Within the MBM group, steroid treatment (HR=2.5, 95% CI 1.3-5.0, p=0.006) was associated with poor OS, whilst treatment with single agent ICB (HR=1.9, 95% CI 0.86-3.9, p=0.11), symptomatic first presentation of MBM (HR=1.5, 95% CI 0.76-2.8, p=0.25) and anti-seizure drug treatment (HR=1.74, 95% CI 0.89-3.4, p=0.10) were not. Amongst all patients carriage of a BRAF mutation was associated with increased risk of MBM (OR 2.49, 95% CI 1.4-4.4, p=0.0007), and increased propensity to new brain metastases on ICB treatment (OR 2.5, 95% CI 1.1-5.9, p=0.036). Analysis of blood and plasma samples demonstrated that patients with MBM have altered haematological profiles, with raised NLR and increased plasma glial fibrillary acidic protein levels, reinforcing the distinct systemic features of MBM. Conclusions In this real-world cohort of patients receiving ICB for metastatic melanoma, the presence of MBM did not associate with worse OS. Conversely, baseline corticosteroid use was adversely prognostic. Intriguingly, plasma GFAP was significantly elevated in patients with MBM and correlated with the burden of intracranial disease, highlighting a potential role for GFAP as a candidate biomarker for MBM in high-risk surveillance. Our observations indicate the adversely prognostic weight historically attached to M1d disease is no longer applicable in the ICB era.

Brazil experienced its worst dengue epidemic in 2024, with an increase in severe outcomes among elderly individuals, highlighting the need for vaccination strategies informed by population immunity. We reconstructed state- and age-specific immune profiles by fitting an age-structured catalytic model to dengue surveillance data from 2000-2025. This inferred immune profile was incorporated into an SIR-type transmission model to project disease burden and to evaluate the public health impact of vaccine allocation strategies. We observed substantial spatial heterogeneity in accumulated immunity, which was closely associated with projected burden and optimal allocation. Strategies prioritizing states with lower historical incidence and larger susceptible populations yielded greater benefits. Under limited vaccine supply, targeting children resulted in the greatest reductions in DALYs, whereas targeting elderly populations achieved smaller DALY reductions but larger reductions in mortality. We further showed that accelerated vaccine supply markedly increased impact, while allocation choices remained critical when availability was constrained.