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Neovascular glaucoma (NVG) represents one of the most severe forms of secondary glaucoma and is characterized by an aggressive clinical course, a high risk of irreversible vision loss, and substantial variability in treatment outcomes. At the same time, the roles of systemic inflammation, ocular microcirculation, and neovascularization of the iridocorneal angle (according to the Weiss D. classification, 1978) in determining the long-term prognosis remain insufficiently investigated. To identify clinical, microcirculatory, and systemic inflammatory predictors of long-term treatment effectiveness in secondary NVG and to compare the outcomes of surgical interventions and diode transscleral cyclophotocoagulation depending on the stage of iridocorneal angle neovascularization. A multicenter retrospective cohort study included 87 eyes with ischemic NVG secondary to proliferative diabetic retinopathy or retinal vein occlusion treated between 2018 and 2024 in Ukraine and Moldova. Patients were divided into a surgical group (n=39) and a diode transscleral cyclophotocoagulation group (n=48). Clinical parameters, systemic inflammatory indices (SII, SIRI, AISI), HbA1c, cardiovascular comorbidity, and the rheographic coefficient (RQ), a functional microcirculation marker, were analyzed. Treatment success was defined as intraocular pressure control with stabilization of visual acuity, absence of rubeosis progression, and no need for additional invasive surgery. Multivariable logistic regression and ROC analysis were performed. Treatment effectiveness was strongly associated with the stage of iridocorneal angle neovascularization. In the early stages, both approaches showed high success rates, whereas in the advanced stages, surgical outcomes declined markedly. In multivariable analysis, surgery increased the odds of success more than fivefold (OR=5.4; p=0.003), whereas advanced angle stages reduced it nearly sixfold (OR=0.18; p=0.007). Higher systemic inflammation was associated with poorer prognosis (SII OR=0.76; p=0.009), whereas better microcirculation was associated with improved outcomes (RQ OR=1.42; p=0.023). The combined predictive model demonstrated good discrimination (AUC = 0.84; 95% CI, 0.74-0.92). In the present study, long-term outcomes of neovascular glaucoma were shown to be determined by the complex interaction between the stage of iridocorneal angle neovascularization, systemic inflammation, and ocular microcirculation. Our findings indicated that the Weiss stage is a key morphological factor that modifies treatment effectiveness. In contrast, systemic inflammatory indices (SII, SIRI, AISI) reflect the underlying biological burden of disease and are associated with poorer prognosis. In contrast, higher values of the microcirculatory parameter (RQ) were significantly associated with more favorable treatment outcomes, likely reflecting preserved perfusion capacity and a lower degree of ischemic tissue damage. This observation is consistent with the concept of ischemia-driven progression in NVG. Importantly, integrating these parameters into a multivariable model demonstrated good discriminative performance (AUC = 0.84), supporting the value of a combined clinical-biological approach to risk stratification. Taken together, these results suggest that NVG should be considered not only a localized ocular disorder but also a systemically influenced condition in which the interplay among angiogenesis, inflammation, and microcirculatory dysfunction determines individual treatment response. Long-term outcomes in neovascular glaucoma appear to be determined by the interaction between the stage of iridocorneal angle neovascularization, systemic inflammation, and ocular microcirculation. Surgical treatment provides the greatest benefit in early disease, whereas cyclophotocoagulation remains a stable option in advanced stages. Combined clinical-biological modeling may support personalized treatment selection in NVG.

Histological grading is a key predictor of progression in non-muscle-invasive bladder cancer (NMIBC). The WHO 1973 three-tier system is limited by heterogeneity within the G2 category, whereas the WHO 2004/2016 binary classification reduces prognostic resolution by grouping biologically diverse tumours into broad low-grade (LG) and high-grade (HG) categories. We aimed to evaluate the prognostic performance of hybrid grading systems compared with WHO 2004/2016, while further characterizing the histomorphological continuum of non-invasive papillary urothelial carcinoma. Non-invasive papillary urothelial carcinomas (2012-2023; n&#x2009;=&#x2009;472) were reviewed and reclassified by two urological pathologists according to WHO 2004/2016, hybrid three-tier and four-tier systems, and an investigational five-tier framework (Grades I, IIA, IIB, IIIA, IIIB) integrating architectural, cytological and proliferative features. Primary endpoints were recurrence, grade progression and T1+ stage progression, assessed using ROC analysis, Cox proportional hazards regression and model-performance metrics (AIC, BIC, C-index). Increasing morphological atypia was associated with larger tumour size, greater multifocality and progressively higher progression risk, with events concentrated in Grades IIIA and IIIB. All systems showed limited recurrence discrimination (C-index 0.54-0.56). For T1+ progression, discrimination improved with increasing stratification (AUC 0.754 for WHO 2004/2016 vs. 0.815, 0.828 and 0.827 for the hybrid three-tier, four-tier and five-tier systems, respectively; all P&#x2009;<&#x2009;0.001). The Hybrid 3-Tier model achieved the most favourable AIC and BIC, while the five-tier model yielded the highest C-index (0.818). Hybrid grading systems improve progression-risk stratification in non-invasive papillary urothelial carcinoma compared with WHO 2004/2016, with most benefit achieved by the Hybrid 3-Tier framework. These findings support the concept of a histomorphological continuum of progression risk and favour continued refinement of biologically informed hybrid grading for NMIBC risk stratification.

Recombinant measles virus (rMeV) vectors are promising platforms for vaccine development against emerging infectious diseases due to their safety, stability, and potent immunogenicity. However, conventional rMeV rescue systems frequently exhibit low efficiency, thereby constraining their scalability and throughput. In this study, we developed a modular, helper-virus-free and high-efficiency rescue platform based on an orthogonal transcription system utilizing orthogonal promoters and engineered RNA polymerases fused to an mRNA capping enzyme. This innovative system facilitated robust cytoplasmic manufacture of both genomic and auxiliary components, eliminating the need for helper virus co-infection (such as modified vaccinia virus) and enhancing rescue efficiency by more than 50-fold relative to traditional rescue approaches. Utilizing this technology, we demonstrated the versatility of the platform by successfully generating six rMeV-based vaccine antigen candidates from influenza virus, Pseudomonas aeruginosa, and Brucella spp. All rescued vaccine candidates exhibited stable transgene expression, sustained replication, and strong antigen production. Immunization studies in golden Syrian hamsters verified that the vaccine candidates elicited high titers of neutralizing and antigen-specific antibodies without any observable adverse effects. These results demonstrate that our orthogonal transcription-based platform facilitates the efficient and safe production of rMeV vectors and provides a proof-of-concept methodological framework for the rapid development of vaccine candidates.

The relationship between lipid metabolism and intracerebral hemorrhage (ICH) is not fully understood, particularly regarding its potential contribution to disease initiation and progression. Accordingly, this study employed machine learning methods to identify and validate pivotal lipid metabolism-related genes in ICH. We integrated our mouse mRNA sequencing data with the ICH-associated datasets GSE216607 and GSE200575. Lipid metabolism related genes were obtained from the MSigDB database. The analysis of differentially expressed genes (DEGs), Weighted correlation network analysis (WGCNA) and intersecting with lipid metabolism-related gene sets to screen the DEG of lipid metabolism-related in ICH. Multiple machine learning (ML) algorithms and a protein protein interaction network were then used to further identify key genes, which were subsequently validated in an independent dataset. Enrichment analysis, immune infiltration analysis, and clustering analysis were conducted to explore their potential biological functions. A mouse ICH model was then established and evaluated by MRI, HE staining, and Nissl staining. Quantitative PCR, immunofluorescence, and Western blotting were performed for preliminary experimental validation of the key genes and pathways. In ICH, 84 differentially expressed lipid metabolism-related genes were identified, with enrichment mainly observed in lipid metabolism and the PPAR signaling pathway. By integrating multiple ML algorithms with protein protein interaction network analysis, Plin2, Cd36, and Abca1 were ultimately identified as three key genes. Validation in an independent dataset showed that all three genes were significantly upregulated in the ICH group. In the mouse ICH model, the mRNA expression levels of these genes were also markedly increased, consistent with the bioinformatics results. In addition, the PPAR signaling pathway was implicated by enrichment analysis and preliminary validation. Abnormal lipid metabolism may be involved in the pathogenesis and progression of ICH, and Plin2, Cd36, and Abca1 may serve as potential biomarkers associated with ICH-related lipid metabolic changes.

Scapular dyskinesis, further characterized within the broader concept of scapulothoracic abnormal motion (STAM), is common in both symptomatic and asymptomatic overhead athletes. While STAM type 3 (winging) is a distinct pathological entity, types 1 and 2 remain less well defined and may represent sport-related adaptations rather than disease. The clinical relevance, prevalence, and sport-specific patterns of these conditions are still unclear. The objectives of this study were to: (1) evaluate the prevalence of STAM types 1 and 2 in the dominant and non-dominant shoulders of professional overhead athletes compared with a control population; (2) identify clinical consequences associated with STAM; (3) assess the impact of different overhead sports on STAM; and (4) explore the association between STAM and other shoulder conditions, such as glenohumeral internal rotation deficit (GIRD) and hyperlaxity. 45 professional in season overhead athletes (15 water polo, 16 basketball, and 14 CrossFit) were included in the study group. Control group consists in 21 volunteers with no or minimal shoulder involvement in sport activity. STAM type was diagnosed using clinical examination and the shoulder flexion resistance test. The shoulder passive range of movement, pain, hyperlaxity, GIRD, American Shoulder and Elbow Surgeons (ASES) score, and the Kerlan-Jobe score were also recorded. A statistical analysis was run to identify any differences in STAM between study and control groups, the clinical role of STAM types, any clinical factor associated to STAM, and the differences between the 3 selected types of overhead sports. STAM type 1 was found more frequent in the dominant shoulder of athletes than in the control group (q = 0.045). No specific factor associated with scapular dyskinesis was identified in the univariate or multivariate regression analysis. However, STAM type 2 was associated with general joint hyperlaxity and the Beighton score (q = 0.04). A diagnosis of STAM type 1 or type 2 was not associated with higher pain scores, a higher GIRD rate, or lower Kerlan-Jobe or ASES scores. STAM type 1 was more common in the dominant shoulder of professional overhead athletes. In contrast, STAM type 2 was observed similarly in the dominant and non-dominant shoulders in both the study and control groups and was associated with generalized joint hyperlaxity. STAM types 1 and 2 were not associated with pain, GIRD, ASES score, or Kerlan-Jobe score in this cohort. These findings support epidemiologic differences between STAM subtypes, but do not establish causal mechanisms, distinct biological etiologies, or definite clinical relevance.

Background The increasing demand for mercury-free restorative materials has encouraged the development of alternative biomaterials with improved mechanical strength and biocompatibility. Aim To compare the mechanical and biological performance of carbon nanotube (CNT)- and graphene oxide (GO)-reinforced epoxy composites as potential restorative materials. Objectives To fabricate epoxy nanocomposites with varying CNT (1%, 2.5%, 5%) and GO (5%, 10%, 15%) concentrations and evaluate their tensile, compressive, nano-mechanical, and cytotoxic characteristics. Materials and methods Epoxy composites were synthesized using epoxy resin and hardener systems incorporated with CNT and GO nanofillers. Mechanical properties were evaluated through tensile, compressive, and nanoindentation testing, while cytotoxicity on human gingival fibroblasts was assessed using the crystal violet assay. Results GO-reinforced composites showed higher modulus and tensile strength than CNT-reinforced systems in this limited sample (n=2 per group). The apparent optimum reinforcement occurred at 10% GO and 2.5% CNT. Conclusion Controlled incorporation of CNTs and GO improved the mechanical performance of epoxy composites and was not associated with marked short-term cytotoxicity at lower loadings in a preliminary screening assay.

Although modern commentators date systematic study of sleep and immunity to the late 1970s, both medical and popular writing from the late 19th and early 20th centuries reveal a much earlier awareness of the immunological effects of sleep and sleep deprivation. This article demonstrates how historical actors conceptualized sleep as integral to bodily defense, thereby revealing a key part of the immune imaginary. The authors map the development of conceptual and experimental linkages between sleep and biological immunity from the late 19th century to the 1920s across the Anglophone tradition, revealing how popular writing reimagined this emerging biological connection, foregrounding representations of sleep as a vital mechanism through which individuals could fortify the body against diverse forms of invasions. The authors then identify a reorientation in popular discourse: a movement from an emphasis on the individual body towards a broader concern with the social body. Through examining this shift, it is possible to trace a reconfiguration of immunity away from the biological towards one concerned increasingly with protection from social, moral, and environmental factors.

Parkinson's disease (PD) and rheumatoid arthritis (RA) are two common chronic diseases, but the potential links between them and the common molecular mechanisms remain largely unknown. The purpose of this study was to explore the potential association and common genetic signatures between RA and PD. Based on the data from NHANES 2001-2016 (n=27,215) and real-world clinical setting (n=209), logistic regression analysis was used to evaluate the association between PD and RA. Subsequently, the potential molecular mechanisms linking between PD and RA were explored based on transcriptomic data. Based on data from NHANES and real-world clinical settings, this study confirmed that RA was significantly associated with an increased risk of PD. Based on the transcriptome data, 79 common DEGs and three key genes (GNB2L1, HSPA9, RPA1) were identified. Functional enrichment analysis revealed that common DEGs were significantly enriched in multiple immune-related biological pathways, activation of innate immune response, T cell receptor signaling pathway, and PI3K-Akt signaling pathway. Based on GSVA and GSEA analysis, this study also identified three signaling pathways (MTORC1_SIGNALING, OXIDATIVE_PHOSPHORYLATION and MYC_TARGETS_V1) that may play a key role in the occurrence and development of PD and RA, and are regulated by GNB2L1, HSPA9 and RPA1. Regulatory network analysis identified key miRNAs (for example, hsa-miR-143-3p, hsa-miR-128-3p) and TFs (for example, MYB) that may coregulate these key genes. The nomogram model constructed based on these genes showed favorable predictive performance for both disease. The results of this study showed a significant association between PD and RA. Furthermore, it was revealed that GNB2L1, HSPA9, and RPA1 may have complex regulatory mechanisms in PD and RA, providing new insights into the common molecular basis and therapeutic targets of these two different diseases. Notably, these associative findings from epidemiological and transcriptomic analyses require further experimental validation.

Social disconnection, including loneliness and social isolation, is increasingly recognized as an important social determinant of adult health, but its relationship with chronic disease-related outcomes remains dispersed across disease areas and study designs. This systematic review aimed to synthesize evidence on the associations of loneliness and social isolation with chronic disease-related outcomes among adults in community, primary care, outpatient, registry-based, and population-based settings. PubMed/MEDLINE, Scopus, Web of Science, Web of Science East Mediterranean Region, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, the Cochrane Library, Google Scholar, and reference lists were searched from database inception to May 10, 2026, for original studies reporting loneliness or social isolation in relation to cardiovascular, metabolic, respiratory, renal, frailty-related, behavioral, biological, functional, quality-of-life, morbidity, or mortality outcomes. Thirty-one studies were included and synthesized narratively because of heterogeneity in populations, exposure measures, outcomes, study designs, follow-up periods, adjustment strategies, and reported effect estimates. The included evidence was mainly observational and suggested associations between loneliness, social isolation, and a broad range of adverse chronic disease-related outcomes, with more consistent associations reported for cardiovascular disease, cardiometabolic conditions, chronic kidney disease, frailty, functional impairment, and mortality. Behavioral pathways, reduced self-management, poorer preventive behavior, lower medication adherence, and inflammatory mechanisms may partly explain these associations, although causal inference remains limited. Loneliness and social isolation appeared related but not interchangeable, as both reflect social disconnection, although loneliness is subjective, while social isolation is more objective and structural. These findings support further evaluation of social disconnection assessment in adults with or at risk of chronic disease, particularly in primary care and outpatient settings. Future research should use standardized exposure measures, repeated assessment, and stronger longitudinal, registry-linked, or intervention designs to clarify temporal directionality and determine whether improving social connection can improve chronic disease outcomes.

The impact of Mycoplasma contaminations on in vitro test systems has been extensively discussed and in vitro studies have demonstrated various effects on the physiology of the contaminated cell line. Thus far, little is known about the effect of biologically active substances, such as viruses produced in contaminated cell lines on primary immune cells. Therefore, the aim of the present study was to pinpoint the impact of Mycoplasma contamination on human innate immune cells. To address this, myeloid dendritic cells (mDC) and two types of macrophages (type M1 and M2) were in vitro differentiated from healthy donors and treated with different volumes of cell-culture supernatant from Mycoplasma-contaminated VeroE6 cells (SN(M)). Depending on the cell type, Mycoplasma contamination mediated a decrease in viability and the pre-activation of the immune cells. Surprisingly, small amounts of SN(M) were sufficient to induce the secretion of massive amounts of pro-inflammatory interleukin (IL)-6 and, to a lesser extent, tumor necrosis factor (TNF)-&#x3b1; and interleukin (IL)-10. Moreover, SN(M) co-stimulation of cells treated with a variety of toll-like receptor (TLR) ligands and different RNA-encoded viruses differentially altered their activation status, depending on the analyzed markers, cell types, and stimuli. Furthermore, SN(M) co-treatment strongly influenced the induced cytokine profile of mDC as well as M1 and M2 macrophages upon treatment with various stimuli, especially upon viral infection. In line with this, a batch of SARS-CoV-2 produced in Mycoplasma-contaminated VeroE6 cells induced high levels of IL-6 and TNF-&#x3b1; while treatment with the non-contaminated virus stock did not result in expression of cytokines. Our data indicate that Mycoplasma contamination has a major impact on the experimental outcome of infection experiments using human immune cells and therefore can result in misinterpretation of experimental data.

There is a growing interest in identifying potential biomarkers that can objectively serve as tools for diagnosis, monitoring, and treatment of ocular chronic pain. Although pain is a biological warning signal absolutely necessary for our survival, when it lasts for 3 or more months it becomes chronic and then it is considered a disease by itself. Chronic pain is a very disabling condition/disease which highly impairs the quality of life of patients. Development of ocular chronic pain, persistent and of high intensity, is present in some patients with dry eye disease (DED), or it can be triggered by some pathological events or after surgical procedures. However, in many of these cases the ocular clinical examination is apparently normal, and the explanation of that pain is not obvious. This type of pain is also difficult to treat because its pathophysiological mechanisms are not completely understood yet, and there are no standard criteria for its diagnosis. Several tear fluid biomarkers have been presented for different ocular diseases, and also for non-ocular, systemic diseases. Different studies have addressed the analysis of tear molecular profiles, including proteins, cytokines and neuromediators such as IL-9, MIP-1&#x3b1;, IL-10, IL-8, TNF-&#x3b1;, IL-6, Fractalkine, IL-1RA, Substance P, CGRP, NPY, and NGF levels associated with the presence of chronic ocular pain. Additionally, the preoperative tear levels of CGRP have been shown as predictive risk factor for ocular pain development after refractive surgery. These specific molecular profiles might help to explain the differences in symptomatology and clinical parameters in patients suffering from ocular pain and to identify those subjects more prone to develop it. Understanding the molecular bases underlying ocular pain will help in the search for effective, selective, and personalized therapies.

Studying fish reproductive biology provides critical insights into population dynamics, supporting effective fisheries management and wildlife conservation. Although the yellowfin snapper Lutjanus xanthopinnis was recently identified as a new species, its reproductive traits across the southern South China Sea remain poorly understood. This study elucidated the reproductive biology of L. xanthopinnis off Borneo and Brunei Darussalam, including spawning seasonality, gonadal development, sex ratio and fecundity. A total of 385 specimens were examined monthly over a one-year period. The overall sex ratio was 1.16:1, indicating a stable regional equilibrium (Chi-square test, p&#x2009;>&#x2009;0.05). Based on monthly fluctuations in the gonadosomatic index (GSI) and histological analysis, both sexes exhibited a prolonged, nearly year-round spawning pattern; females showed a distinct peak from October to August, while males remained mature year-round. The estimated total length at 50% maturity (L 50) was nearly identical between the sexes (18.3&#x2009;cm for females; 18.8&#x2009;cm for males), which is generally smaller than in related Lutjanidae species. Total fecundity ranged from 8000 to 65,000 eggs and showed no significant correlation with maternal body size. Contrasting these findings with recent data from adjacent regional populations reveals remarkable intraspecific plasticity in the life-history strategies of L. xanthopinnis. Unlike neighbouring populations that exhibit monsoon-restricted spawning, pronounced intersexual size differences and male-biased sex ratios, the Brunei population adopts a balanced, continuous reproductive regime. These striking intraspecific variations demonstrate that localised environmental conditions and oceanographic regimes drive significant ecological and evolutionary adaptations in the life cycle of coral reef fishes, even within closely situated geographic regions.

While the systemic anti-inflammatory benefits of dietary polyphenols are well-established, the specific activities of structurally diverse polyphenols remain unclear. This study aimed to evaluate the regulatory capacity of plant polyphenols on inflammatory cytokines based on the affinity differences between compounds and their targets. As ulcerative colitis (UC) is characterized by intestinal inflammatory infiltration, it was selected as the entry point for this preliminary exploration. We integrated data on the intervention of 39 plant-derived bioactive components in UC from existing studies to construct a foundational dataset for the model (105 datasets in total). Based on the available data, inflammatory cytokines (TNF-&#x3b1;, IL-6 and IL-1&#x3b2;) were included as dependent variables. To enhance the assessment of intestinal inflammation, the disease activity index scores and colon length changes were also incorporated as dependent variables. Following a preliminary feasibility assessment via multiple linear regression, we developed the MPAI-SG model using a multilayer perceptron algorithm to enhance prediction accuracy. The model's performance was validated through independent studies on polyphenol-intervened UC mice. The results indicated that predicting effects based on the affinity differences between compounds and targets is feasible. The MPAI-SG model (R2 = 0.464-0.787) successfully predicted the effects of plant compounds on serum inflammatory cytokines in UC mice. Furthermore, the MPAI-SG model was utilized to predict the regulatory potential of 402 plant bioactive components on intestinal inflammation in UC mice. Leveraging the Phenol-Explorer database, 350 common foods were ranked, identifying 142 potential food ingredients for UC intervention, thereby providing a reference for dietary management of UC.

Atrial fibrillation (AF), one of the most common cardiac arrhythmias worldwide, carries a high risk of severe complications. Patients diagnosed with paroxysmal atrial fibrillation (PAF) may progress to persistent atrial fibrillation (PerAF) following a period of time. This study aimed to identify metabolites associated with PerAF using machine learning (ML) and predict the probability of PAF progressing to PerAF, enabling the adjustment of subsequent treatments in clinical practice. AF patients without any anticoagulant therapy within the last 7 days were enrolled between July 2020 and July 2022 at two hospitals in China. Targeted metabolomic profiling was performed on the participating patients' plasma. Differential metabolites and clinical features were identified through univariate and multivariate analyses. Patients were divided into discovery and validation cohorts (70%:30%). Four ML models (logistic regression, random forest, XGBoost, and LightGBM) were developed for PerAF prediction. Model predictive performance was measured mainly using the area under the curve (AUC). One hundred patients (65 PerAF, 35 PAF) were enrolled. Eight metabolites (kynurenine, N-A cetylaspartic acid, glyceric acid, adipic acid, citramalic acid, malic acid, isocitric acid, and oxoglutaric acid) and two clinical features (NT-proBNP and uric acid) were significantly associated with PerAF. Pathway enrichment analysis highlighted alterations in the citrate cycle and glyoxylate/dicarboxylate metabolism. XGBoost was chosen for establishing the final model since its predictive performance outperformed that of the other algorithms. The model based on clinical parameters, metabolites, and demographics achieved the highest AUC in both the discovery cohort (0.751 (95% CI [0.631~0.867])) and validation cohort (0.985 (95% CI [0.940~1.000])). A simplified model with three features (NT-proBNP, citramalic acid, and uric acid) retained robust performance. This study identified eight PerAF-related metabolites via targeted metabolomics and ML, and developed accurate predictive models (including a simplified, clinically feasible model) with favorable predictive performance for PerAF risk stratification. Future directions should include large-scale multi-center external validation, comprehensive adjustment for potential confounding factors, and the application of multiple metabolic platforms to deeply explore AF-related metabolic alterations.

Aging is a systems-level process linking metabolic dysfunction, inflammation, impaired repair, frailty, and multimorbidity, whereas existing pharmacological strategies usually optimize disease-specific endpoints such as weight loss or HbA1c rather than aging-related trajectories. We developed an SBML-compliant quantitative systems pharmacology (QSP) model in which aging is represented as a dynamic, pharmacologically modifiable endpoint. The model integrates four coupled layers: metabolic/pharmacodynamic responses to GLP-1 receptor agonism, SGLT2 inhibition, metformin and rapamycin; adverse-event dynamics; aging states including damage accumulation, repair capacity, frailty and biological age gap; and biomarker outputs including GDF15, cystatin C, leptin, adiponectin and estimated glucose disposal rate. The semaglutide submodel was calibrated against published STEP trial endpoints, and Bayesian hierarchical meta-analysis, global sensitivity analysis, practical identifiability analysis and internal consistency checks were used to assess model behavior. The calibrated model reproduced semaglutide-associated weight loss, HbA1c reduction and transient nausea within pre-specified error benchmarks. Bayesian meta-analysis confirmed strong metabolic effects for semaglutide, moderate glycaemic effects for SGLT2 inhibitors and metformin, and a near-zero HbA1c effect for rapamycin. Sensitivity analysis revealed largely orthogonal metabolic and aging parameter spaces. Combination simulations identified two mechanistically distinct optima: GLP-1 receptor agonist plus SGLT2 inhibitor plus metformin for metabolic improvement, and GLP-1 receptor agonist plus SGLT2 inhibitor plus rapamycin for aging-related benefit. Metabolic optimisation and aging optimisation are therefore mechanistically distinct objectives that do not converge on the same drug combination. These predictions are hypothesis-generating and require external validation against independent longitudinal datasets and clinical safety evaluation before translation to treatment recommendations.

Chronic Kidney Disease (CKD) is a significant public health problem associated with considerable morbidity and mortality. It is known to cause retinal vascular changes and retinopathy that reflects changes occurring in the kidneys. Optical coherence tomography (OCT) is a promising biomarker for assessing retinal changes associated with CKD. This study was conducted to evaluate retinal alterations in patients with CKD using spectral-domain optical coherence tomography (SD-OCT), correlate these findings with biochemical parameters to facilitate early screening and timely detection, and assess disease progression. This single-centre, cross-sectional study included 60 eyes of 60 patients with stage 3, 4, or 5 CKD. Data collected included age, sex, glycaemic status, serum electrolytes, blood urea nitrogen (BUN), and serum creatinine. Fundus examination and various OCT parameters were measured. Central retinal thickness (CRT) and central choroidal thickness (CCT) were measured manually at the subfoveal region. Automated segmentation was used to measure retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) thicknesses across all quadrants and sectors using SD-OCT. Descriptive and inferential statistical analyses were applied to assess significance. Most patients were in Stage 3 CKD, with the majority having a disease duration of 1-3 years. Mean retinal thickness reduced from stage 3 to 5 with no statistical significance, while choroidal thickness remained preserved. Inferior RNFL thickness declined significantly with worsening CKD, whereas temporal RNFL and GCC showed borderline significance. Retinal parameters did not differ by CKD duration. Elevated HbA1c was associated with increased retinal thickness and thicker inferior RNFL. Both hypernatremia and hyperkalemia were associated with reduced retinal thickness. A higher glomerular filtration rate (GFR) was positively correlated with inferior RNFL thickness. The findings of this study suggest that chronic kidney disease is associated with progressive neuroretinal changes, particularly thinning of the inferior retinal nerve fibre layer, which may reflect underlying microvascular and neurodegenerative processes occurring in CKD. The preservation of choroidal thickness despite declining renal function indicates that neuroretinal alterations may precede detectable choroidal changes. The observed associations between OCT parameters and biochemical markers, including HbA1c, serum sodium, potassium, and GFR, further support the influence of systemic metabolic and renal status on retinal structure. The study highlights that chronic kidney disease is associated with neuroretinal alterations that become more pronounced as disease severity increases. Optical Coherence Tomography has emerged as an important biomarker for evaluating these retinal changes. Further, by correlating OCT findings with biochemical parameters, we can evaluate the impact of systemic parameters in CKD on the retina. Therefore, OCT is an important tool in CKD that helps with screening, monitoring, and assessing disease progression.

Hepatocellular carcinoma (HCC) still has limitations such as tumor resistance, recurrence, and poor prognosis. Therefore, the development of anticancer drugs with mechanisms of action is of great significance for the treatment of HCC. In this study, we identified KZL-064, a 2-trifluoromethyl-4-aminoquinazoline derivative, which markedly inhibits HCC cell proliferation, migration, and invasion, induces apoptosis and G2/M arrest, and, in MHCC97-H xenograft mice, oral administration achieves tumor suppression comparable to that of sorafenib without significant toxicity. Through virtual screening, molecular docking, cellular thermal shift assay (CETSA), and biologic layer interferometer (BLI), we identified histone deacetylase 1 (HDAC1) as a direct binding target. Knockdown of HDAC1 partially attenuates pro-apoptotic and cell-cycle effects, yet does not impair anti-migratory/invasive activities nor completely abolish overall efficacy. Collectively, KZL-064 emerges as a promising lead, and its anti-proliferative action likely involves multi-target mechanisms engaging HDAC1 and p53-associated apoptotic signaling, offering a conceptual framework for HCC therapy.

Extracorporeal shockwave therapy (ESWT) is widely applied to manage musculoskeletal disorders, including shoulder pathologies. However, the optimal therapeutic dosage for adhesive capsulitis (AC) remains unclear. This study aimed to evaluate the dose-response relationship of ESWT in patients with AC. In this randomized controlled trial, 48 patients with AC refractory to conservative management were assigned to receive a single session of either basic-dose (3,000 pulses) or high-dose (6,000 pulses) ESWT. Shoulder range of motion was assessed at baseline, immediately after treatment, and at 1, 2, 4, 8, and 12 weeks. Functional outcomes were evaluated at 12 weeks using the Constant Murley score. Subgroup analysis was performed based on baseline abduction (cutoff: 90&#xb0;). At 12 weeks, the high-dose group demonstrated significantly greater improvements than the basic-dose group in forward flexion (P < .001), abduction (P < .001), external rotation (P = .004), and internal rotation (P = .001). The largest changes occurred immediately after treatment. Subgroup analysis showed that high-dose ESWT resulted in superior gains in forward flexion, abduction, and internal rotation across baseline abduction strata, whereas no significant between-group difference was observed for external rotation. High-dose ESWT provided significantly enhanced recovery of shoulder range of motion and function compared with a basic-dose protocol in patients with AC. These findings support a dose-response relationship; however, results should be interpreted as short-term outcomes given the 12-week follow-up and absence of a control group.