Purpose: To compare the ocular alignment of children with literacy-based learning difficulties to at-level peers. Methods: Australian primary-school-aged children were recruited to two groups according to learning difficulty status: at-level group (ALG and learning difficulties group (LDG). Cover test, prism, and alternate cover test, convergence near point, accommodation, fusional ranges, near and distance visual acuity, stereoacuity, and ocular motility were assessed at a single visit in 2023. Results: Eleven children (aged 7 to 12 years, 68.2% female) were recruited in each group. A latent deviation of small angle was observed at near in 81.8% (n = 9, median -3.1 PD) of children in the learning difficulties group but only 36.4% (n = 4, median -0.4 PD) in the at-level group (p = .080). The absolute magnitude of deviation for near was also larger in the LDG (n = 11, 6 PD) than the ALG (n = 11, 0 PD, p = .055). Reduced accommodative near point binocularly (p = .024), stereoacuity at near (p = .009), and near vision (oculus dexter [OD] p = .010, oculus sinister [OS] p = .053) were observed in the learning difficulties group. Conclusions: Latent deviations may be more prevalent among children with literacy-based learning difficulties. Accommodative near point, stereoacuity, and near vision may be reduced in this patient cohort. The differences found between the groups in this study indicate that clinicians should include assessment of accommodation, near vision, stereoacuity, and eye position when testing the vision and binocular vision of children with literacy-based learning difficulties.

Positive surgical margins (PSM) after radical prostatectomy are associated with biochemical recurrence, although margin status reflects a combination of tumour-related, anatomical, and operative factors. We aimed to derive and internally validate an interpretable nomogram that accommodates non-linear predictor effects and estimates postoperative PSM probability after laparoscopic radical prostatectomy (LRP) or robot-assisted radical prostatectomy (RARP). We retrospectively analysed 376 patients with prostate cancer who underwent LRP or RARP and had a documented postoperative margin status. The candidate set included demographic characteristics, indices of preoperative tumour burden, operative variables, comorbid conditions, and postoperative pathological findings. Least absolute shrinkage and selection operator (LASSO) regression was used for initial predictor reduction. Correlation matrices, variance inflation factors, and sensitivity analyses across Top-N predictor sets were used to examine redundancy, stability, and model size. Restricted cubic splines (RCS) were applied to continuous predictors to assess departures from linearity. The selected predictors were entered into multivariable logistic regression. Model performance was evaluated by receiver operating characteristic analysis, calibration plots, Brier scores, and decision curve analysis. A total of 376 patients with prostate cancer were included, of whom 155 (41.2%) had positive surgical margins (PSMs). Multiple margin sites were the most common pattern of PSM involvement (n = 91), followed by the apex (n = 35), base (n = 15), and lateral or posterolateral margins (n = 10). The PSM rate was 33.9% (83/245) in patients with pT2 disease and 68.8% (66/96) in those with pT3 disease. The corresponding PSM rates were 34.8% (49/141) for laparoscopic radical prostatectomy (LRP) and 45.1% (106/235) for robot-assisted radical prostatectomy (RARP). LASSO selection, feature-subset optimization, and subsequent multivariable modeling indicated that perineural invasion, the proportion of positive biopsy cores, seminal vesicle invasion, surgical approach, clinical T stage, lymphovascular invasion, age, and preoperative PSA-related variables contributed to PSM risk prediction. In the final multivariable model, perineural invasion (OR = 2.609, 95% CI: 1.328-5.124; P < 0.05) and the proportion of positive biopsy cores (OR = 1.020, 95% CI: 1.005-1.035; P < 0.05) were significantly associated with PSM. Restricted cubic spline analysis suggested a possible nonlinear association between preoperative log(PSA + 1) and the risk of PSM. The model achieved areas under the receiver operating characteristic curve of 0.801 in the training set and 0.824 in the validation set. The corresponding Brier scores were 0.1778 and 0.1697, respectively. Calibration curves showed overall agreement between predicted probabilities and observed outcomes. Decision curve analysis further indicated that the model provided a positive clinical net benefit across a range of threshold probabilities. The internally validated nomogram separated patients with and without PSM reasonably well, produced acceptably calibrated risk estimates, and may assist postoperative risk stratification after LRP or RARP. Independent validation is necessary before clinical implementation.

Reduced-port robotic surgery, including single-site and single-port approaches, has been increasingly applied in endometrial cancer. However, its clinical value compared with conventional multiport robotic surgery remains uncertain. To systematically compare perioperative outcomes and safety between reduced-port and multiport robotic techniques used for endometrial cancer surgery. Following the PRISMA 2020 recommendations, we carried out a systematic review and meta-analysis that was prospectively registered in PROSPERO (CRD420261443180). Relevant publications were retrieved by searching PubMed, Embase, Web of Science, and the Cochrane Library from their inception until April 2026. Comparative studies evaluating reduced-port robotic surgery (single-site or single-port) against conventional multiport robotic surgery were eligible for inclusion. Treatment effects for continuous variables were pooled as mean differences, while binary outcomes were combined as odds ratios, each with 95% confidence intervals. A random-effects model was consistently applied in all analyses to accommodate anticipated methodological and clinical heterogeneity among the included studies. Eight comparative studies involving 905 patients (350 in the reduced-port group and 555 in the multiport group) met the inclusion criteria. Meta-analysis demonstrated no significant difference in operative time between reduced-port and multiport robotic surgery (MD = 12.54 min, 95% CI: -7.76 to 32.84; P = 0.23). Compared with multiport robotic surgery, the reduced-port approach was associated with modest reductions in estimated blood loss (MD = - 14.83 mL, 95% CI: -29.25 to - 0.41; P = 0.04) and postoperative hospital stay (MD = - 2.12 days, 95% CI: -4.19 to - 0.06; P = 0.04). However, these findings should be interpreted cautiously given the substantial heterogeneity observed across studies. No significant differences were identified in transfusion requirement (OR = 0.55, 95% CI: 0.09-3.16; P = 0.50), conversion to open surgery, intraoperative complications, overall postoperative complications, or Clavien-Dindo grade ≥ III complications (all P > 0.05). Postoperative pain scores were comparable between groups at both 6 and 24 h. Subgroup analysis suggested a potential reduction in early postoperative pain with single-port robotic systems, although this finding did not reach statistical significance in the overall analysis. The available evidence suggests that reduced-port robotic surgery represents a viable option for selected patients with endometrial cancer, with broadly similar short-term perioperative outcomes to conventional multiport surgery. Potential modest reductions in estimated blood loss and postoperative hospital stay were observed; however, the clinical relevance of these differences remains uncertain because of the small absolute effect size and substantial heterogeneity among studies. While no overall benefit in postoperative pain was observed, potential differences between platforms, particularly single-port systems, warrant further investigation.

Limited longitudinal field of view in cone-beam computed tomography (CBCT) remains a significant challenge for image-guided adaptive radiotherapy. We developed a deep learning-based CBCT outpainting framework that synthesizes anatomically consistent extensions beyond the scanned volume. The model employs a dual-branch encoder-decoder architecture that separately encodes CBCT and edge maps derived from planning CT (pCT) and integrates them via attention-guided skip connections and late fusion to preserve structure while accommodating cross-modality differences. The framework was trained and validated using 90 prostate cancer cases, with 20 held-out patients used for quantitative evaluation against four baseline models. The proposed method achieved the lowest absolute volume difference for the clinical target volume at 0.11 ± 0.07 cc and for the planning target volume at 0.05 ± 0.04 cc. It also yielded superior perceptual image quality, with LPIPS of 0.119 ± 0.029 and FID of 54.70. Qualitative assessment confirmed improved soft-tissue continuity and more faithful preservation of anatomical landmarks in both bony and low-contrast regions. These results demonstrate that the proposed framework can restore CBCT longitudinal coverage with high anatomical fidelity, supporting more reliable deformable registration and adaptive radiotherapy workflows in clinical environments constrained by limited-FOV CBCT.

The calcium-sensing receptor (CaSR) plays an important role in calcium homeostasis and multiple physiological regulatory processes, and its Venus flytrap (VFT) domain is a key region for γ-glutamyl peptide binding. In this study, molecular docking, surface plasmon resonance (SPR), and molecular dynamics simulations were integrated to systematically investigate the binding behavior of 400 γ-glutamyl tripeptides with CaSR-VFT. The results showed that all 400 γ-glutamyl tripeptides could be accommodated in the central binding pocket of CaSR-VFT, with binding energies mainly ranging from -6 to -10 kcal mol[-1]. Interaction site analysis indicated that Ser272, Asn102, Arg66, Ser147, Asn64, and Ser170 were the major high-frequency interacting residues, among which Ser272 showed the highest occurrence frequency. The peptides with the strongest and weakest predicted binding abilities, γEYW and γECF, exhibited docking binding energies of -9.863 and -6.05 kcal mol[-1], respectively. After Ser272Ala mutation, the absolute binding energies of γEYW and γECF decreased by 44.02% and 15.50%, respectively. SPR experiments confirmed that both γEYW and γECF could directly bind to purified CaSR-VFT protein, with KD values of 3.3 μM and 329.4 nM, respectively. Molecular dynamics simulations showed that γECF exhibited a more stable hydrogen-bond network and a more concentrated low-free-energy conformational distribution. Overall, this study screened and validated two novel γ-glutamyl tripeptides capable of binding to CaSR-VFT, providing a reference for the screening of CaSR-targeting peptides and the investigation of their binding mechanisms.

Objective.FLASH radiotherapy introduces beam temporal structure at the pulse and sub-pulse scale, whereas most tumor control probability (TCP) models are formulated at the fraction or treatment-course scale. This study developed, a pulse-resolved extension of the published Lee-Rosen time-dependent TCP formulation, here denoted, to connect FLASH beam microstructure, oxygen/radical kinetics, biological repair, and treatment-course repopulation.Approach.TCPLRwas used as the parent treatment-course TCP model because it accommodates variable interfraction timing and kick-off-time-dependent accelerated repopulation. Its conventional cumulative survival term was replaced by a FLASH-aware survival term derived from a reduced-order oxygen/radical ordinary differential equation kernel. Each FLASH fraction was represented as a pulse train. The same oxygen/radical kinetics, lesion-yield calculation, and post-fraction repair layer were also implemented for standard-dose-rate continuous delivery to provide an internal comparator. The implementation was verified against uniform-dose benchmarks reported in the original Lee-Rosen publication describingand then evaluated using exploratory FLASH, repair, pulse-structure, and standard-dose-rate scenarios.Main results.Conventional verification reproduced published benchmark trends, with maximum absolute differences of 1.44, 1.21, and 3.48 percentage points for head-and-neck, breast, and prostate cases, respectively. In a 3 × 8 Gy starter case, calibrated null-FLASH TCP was 0.790. Moderate chemistry and strong radical recombination yielded TCP values of 0.713 and 0.703, respectively, whereas mild oxygen limitation reduced TCP to 0.276. Standard-dose-rate continuous delivery produced negligible oxygen depletion under null and moderate chemistry assumptions, while deliberately oxygen-limited standard-dose-rate cases showed reduced TCP.Significance.This exploratory framework provides a mechanistic treatment-course TCP platform for hypothesis testing in FLASH radiotherapy. It demonstrates how pulse microstructure and continuous standard-dose-rate delivery can be evaluated within the same published variable-timeformulation, while showing that FLASH TCP behavior depends on oxygen/radical kinetic assumptions, pulse structure, repair, and oxygen availability rather than being universally preserved or reduced.

In 2022, the case of Andrea Prudente, an American tourist denied an abortion for a non-viable pregnancy in Malta, catalysed unprecedented social mobilisation, and compelled a legislative review of the country's abortion ban. This paper traces the political and social dynamics that shaped this process, from the initial advocacy to the final, heavily contested legislative outcome. Drawing on Morgan and Roberts' concept of reproductive governance, we examine media content and parliamentary discourses to trace how state actors mediated the conflict between competing moral, and legal frameworks. Our analysis demonstrates that while persistent pressure by pro-choice advocates was instrumental in forcing a legislative review, the government's initial proposed reforms were systematically contested, and ultimately neutralised by a powerful, well-organised anti-choice countermovement. We argue that state actors ultimately capitulated to immense conservative pressures from influential religious and civil society actors. The resulting amendment, which permits termination only under exceptionally restrictive circumstances to save a pregnant person's life, is a stark example of how reproductive governance can accommodate pressure for change while leaving the underlying system intact. This process highlights how legal reform can be critically decoupled from meaningful access, failing to secure genuine reproductive rights. Despite its profound limitations, the amendment constitutes the first-ever legal exception to Malta's absolute ban, proving that such entrenched governance frameworks are not immutable. The Prudente case and the mobilisation it inspired have irrevocably fractured the previous politico-legal consensus, thereby creating a precedent for future legal challenges and continued advocacy for comprehensive reproductive justice in Malta.

Recent advances in systematics and evolutionary biology have revealed extraordinary complexity in phylogenetic diversification, challenged our traditional views of the Tree of Life, and changed our understanding of the nature of phylogenetic entities themselves. These empirical advances call for an updated conceptual basis for phylogenetics. Phylogeny is best conceptualized as a complex multidimensional system - encompassing spatial, temporal, and hierarchical dimensions. The hierarchical dimension confers important but poorly studied influences - such as emergence, constraint, non-linearity, and non-extrapolationism - on phylogenetic possibilities. Spatially and temporally, phylogenetic diversification patterns should be viewed as resulting from multimodal phenomena - i.e., as a consequence of both vertical and horizontal modes of evolution. Further, phylogeny should not be viewed as a single absolute history - it comprises interacting, multi-layered lineage histories (i.e., genomes, cells, organisms, species). Causal interactions and feedback dynamics amongst these dimensions represent a classic biocomplexity system. Therefore, we suggest that this is an opportune time for development of a phylogenetic systems theory. Because our view of phylogeny comprises a complex interacting system of multiple lineage histories, we also argue that a process ontology provides the logical foundation for contemporary phylogenetics. A process ontology framework also reconciles recent observations that the boundaries of biological entities (including the boundaries of genomes, cells, organisms, and species lineages) are fuzzy and open to varying degrees of exchange at various points in their histories. While these fuzzy boundaries accommodate the biocomplexity and multimodal evolutionary processes described above, they also pose challenges for our notions of phylogenetic entities themselves and their biological individuality - leading to exciting new areas of study in systematics, theoretical biology and philosophy of biology.

Frailty is a clinical syndrome of reduced physiological reserve in older adults for which no pharmacological treatment exists and whose cellular basis remains incompletely defined. As life expectancy rises without a comparable extension of healthspan, the absence of a mechanistic account able to guide targeted intervention is a growing clinical problem. The dominant model of primary mitochondrial bioenergetic insufficiency does not accommodate several features of the phenotype. Among the conditions most strongly associated with frailty in aging, obesity, particularly when coupled with sarcopenia, stands out for its rising prevalence and the depth of its systemic metabolic consequences. Drawing on a recent multi-omics characterisation of skeletal muscle in sarcopenic obesity and on the convergent literature in aging metabolism, organelle communication, and redox biology, we propose a complementary framework in which the proximate cellular abnormality of frailty is energetic congestion, a chronic mismatch between substrate input, energetic demand, and the capacity to dispatch the resulting flux through demand-driven oxidative metabolism. In this view the mitochondrion is not failing because fuel is scarce, but because energetic demand declines below the rate at which substrate continues to be delivered, so that substrate persists in relative rather than absolute excess, while mitochondrial adaptability is progressively impaired. The resulting cycle is self-amplifying, anchored in reverse electron transport, and generalises across skeletal muscle, adipose tissue, liver, heart and brain. Strategies that re-engage demand-driven metabolic flux through AMPK activation, substrate restriction, mild mitochondrial uncoupling, modulation of endoplasmic reticulum stress, and clearance of irreversibly congested cells are predicted to produce more durable benefits than energy supplementation, with structured exercise as the prototype of demand-driven recoupling. This perspective offers a path toward a precision pharmacology of frailty grounded in molecular stratification of patients.