Clinical trials in ophthalmology frequently report multiple efficacy and safety outcomes of varying clinical importance analyzed either in isolation or as simple composites. The Win Ratio (WR) is a hierarchical composite metric originally developed to address such limitations in cardiovascular research by integrating outcomes according to their clinical priority. In this study, we assess its potential utility in ophthalmology outcomes with glaucoma surgery as the exemplar.

Retrospective registry-based study.

There are 1257 eyes that underwent a Xen gel stent (Xen) implantation or trabeculectomy (Trab) with a minimum 12 months of follow-up.

Propensity score matching yielded two comparable cohorts (212 eyes each) without significant differences in age, baseline intraocular pressure, number of medications, visual acuity, or visual field mean deviation. A predefined hierarchy of eight adverse outcomes was constructed, headed by loss of light perception vision, secondary glaucoma surgery, followed by early postoperative complications (e.g., hypotony and hyphaema) or bleb needling. Each Xen-Trab pair was evaluated sequentially and classified as a win, loss, or tie.

The overall WR with 95% confidence intervals (CIs) and P value was estimated, and sensitivity analyses examined the robustness of results under alternative outcome hierarchies and random permutations.

The Xen group accumulated fewer wins than Trab (WR 0.83, 95% CI 0.63-1.10, P = 0.19), although the difference was not significant. Differences were driven by higher rates of secondary glaucoma surgery (18.4% vs. 12.7%) and bleb needling within the first 6 months (28.8% vs. 13.2%) in the Xen group, with remaining outcomes occurring infrequently and evenly distributed in each group. Sensitivity analyses with alternative hierarchies yielded consistent results (WR range 0.80-0.98), and random permutations of lower-ranked outcomes clustered around WR 0.77, supporting the consistency of the final outcome.

The WR offers a clinically meaningful, hierarchical approach to comparing multidimensional treatments that respects clinical priorities. Our findings illustrate the potential utility of this metric in the prospective evaluation of trial outcomes in ophthalmology.

The authors have no proprietary or commercial interest in any materials discussed in this article.

Autoimmune disorders have been linked to increased cardiovascular disease (CVD) risk, but it is unclear whether the association is uniform across conditions or is concentrated in specific diseases, and whether inflammatory markers add value in a Middle Eastern primary-care setting. We examined disease-specific associations between autoimmune disorders and recorded CVD, rather than building a prognostic prediction tool.

We conducted a matched cross-sectional analysis of 28,374 adults (9517 with a documented autoimmune disorder - rheumatoid arthritis [RA], systemic lupus erythematosus [SLE], or Hashimoto thyroiditis - and 18,857 age- and sex-matched controls). Because individual matched sets and per-control index dates were not recoverable, associations were estimated with unconditional logistic regression adjusting for the matching variables, using multiple imputation (m = 20) for missing covariates. We fitted nested models (A: traditional risk factors; B: + autoimmune status; C: + C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]), then a disease-specific model. We assessed discrimination (AUC), out-of-sample calibration, and clinical utility (decision-curve net benefit and categorical reclassification), tested age and sex interactions, and compared logistic regression with tuned random forest and XGBoost. Findings are interpreted as cross-sectional associations, not incident-event predictions.

A recorded cardiovascular diagnosis was present in 2991 of 28,374 patients (10.5%). Any autoimmune disorder was associated with CVD across all specifications (Model A OR 1.41, 95% CI 1.29-1.55; Model C OR 1.40, 1.28-1.54). The disease-specific model fitted better than the binary model (likelihood-ratio p = 4 × 10^-40; ΔAIC = 182) and showed marked heterogeneity: SLE was strongly associated with CVD (OR 3.40, 95% CI 2.94-3.94), whereas the adjusted estimate for RA was near the null (OR 1.05, 95% CI 0.94-1.16) and Hashimoto thyroiditis was at most marginally associated (OR 1.19, 95% CI 0.98-1.45). The autoimmune-CVD association was stronger at younger ages (age × autoimmune OR 0.97 per year, p = 4 × 10^-19); disease × sex interactions were not significant. Discrimination was similar across models (AUC 0.823 for Model A to 0.833 for the disease-specific model), and the model was well calibrated out-of-sample (bootstrap-corrected calibration slope 0.997, intercept -0.005, Brier score 0.076). Adding CRP and ESR did not improve net benefit or calibration, and tuned machine-learning models offered no advantage over logistic regression (test-set AUC 0.832 for logistic regression). The clinical value of disease-specific modelling lay in reclassification rather than average discrimination: it correctly moved SLE patients into higher risk categories (event-based net reclassification +0.52) while de-escalating the near-null RA and Hashimoto groups.

In this matched cross-sectional cohort, the association between autoimmune disorders and cardiovascular disease was heterogeneous and driven almost entirely by SLE. The near-null RA estimate should not be read as absence of risk, because the cross-sectional design, over-adjustment for mediators, confounding by indication, and survivor bias plausibly bias it downward; a clinically important RA association cannot be excluded. Point-in-time inflammatory markers added little, and well-calibrated logistic regression performed as well as machine-learning models. Because predictors and the outcome are not temporally anchored, these findings describe disease-specific associations and should not be interpreted as prognostic or causal effects.

Acute coronary syndrome (ACS), as one of the cardiovascular diseases, plays a significant role in patient mortality. Although appropriate diagnostic methods have been introduced for ACS, it still remains a challenge for physicians. Therefore, utilizing additional markers and ratios for the diagnosis of ACS can be beneficial. Hence, our study was conducted with the aim of evaluating the diagnostic value of indices and ratios derived from the complete blood count (CBC) test.

In this retrospective diagnostic accuracy study, 360 patients presenting with acute chest pain to the emergency department of Allameh Bohlool Hospital were evaluated. Patients were classified into ACS (n = 167) and Non-ACS (n = 193) groups based on the final clinical diagnosis. CBC-derived parameters, including leukocyte count, neutrophil count, monocyte count, platelet count, mean platelet volume (MPV), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR), were assessed. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. Multivariable logistic regression models were developed to determine independent associations and assess the incremental diagnostic value of CBC-derived markers beyond clinical variables.

Patients with ACS had significantly higher leukocyte count, neutrophil count, monocyte count, MPV, NLR, and MLR levels compared with Non-ACS patients (all p < 0.01). Among individual biomarkers, neutrophil count demonstrated the highest diagnostic performance (AUC = 0.720; 95% CI, 0.668-0.772), followed by leukocyte count (AUC = 0.704; 95% CI, 0.651-0.758) and NLR (AUC = 0.669; 95% CI, 0.613-0.725). After adjustment for clinical variables, leukocyte count (adjusted OR = 1.64; 95% CI, 1.41-1.91; p < 0.001) and neutrophil count (adjusted OR = 1.68; 95% CI, 1.42-1.99; p < 0.001) remained independently associated with ACS. Addition of leukocyte count to the clinical model significantly improved discrimination (AUC increased from 0.787 to 0.850; ΔAUC = 0.063; DeLong p < 0.001).

In this study, selected CBC-derived parameters, particularly neutrophil count, leukocyte count, and NLR, showed statistically significant but limited discriminatory ability for ACS. These indices may be considered adjunctive inflammatory markers, but their diagnostic performance is insufficient for use as stand-alone tests and should be interpreted alongside clinical assessment, ECG, and cardiac troponin testing.

Fungal infection represents an escalating global health threat, yet effective treatment remains clinically challenging due to the poor solubility, limited bioavailability, and pronounced cytotoxicity of conventional antifungal agents. To overcome these limitations, a self-assembled nanoparticle (ATE NPs) is developed by integrating amphotericin B (AmB), epigallocatechin gallate (EGCG), and tri(phenylboronic acid)-derived crosslinker pentamethyldiethylenetriamine (T-PBA) for efficient fungal eradication and accelerated tissue repair. Benefiting from the strong affinity of T-PBA towards fungal cell wall polysaccharides, ATE NPs exhibit targeted adhesion and prolonged retention at infected lesions. Within the infection-associated mildly acidic microenvironment, the cleavage of boronate ester bonds triggers the controlled release of AmB, disrupting fungal membranes and eliminating pathogens. Meanwhile, EGCG exerts potent anti-inflammatory and pro-healing effects to promote tissue regeneration. Consequently, ATE NPs exhibit robust mucoadhesion, superior antifungal activity, and remarkable wound-healing capabilities both in vitro and in vivo. In murine models of fungal keratitis and cutaneous mycosis, the multifunctional nanosystem effectively suppresses fungal proliferation, mitigates corneal inflammatory damage and accelerates healing. Furthermore, transcriptomic analysis reveals that ATE NPs induce fungal metabolic dysregulation and oxidative stress while favorably modulating host immune responses. Overall, this work provides a promising, biocompatible nanotherapeutic strategy for the integrated management of severe superficial fungal infections.

Ischemia-reperfusion injury (IRI) and acute rejection (AR) limit liver transplantation success. Early growth response 1 (EGR1) mediates stress and inflammation, yet its cellular distribution and potential involvement in adaptive alloimmunity during distinct post-transplant stages remain unclear.

A rat orthotopic liver transplantation model was used to evaluate graft injury and EGR1 spatiotemporal expression during IRI (6-24 h) and AR (5-10 d). Public scRNA-seq data and virtual knockout analysis were used to assess the cellular distribution and potential regulatory role of Egr1. EGR1-overexpressing bone marrow-derived dendritic cells (BMDCs) were co-cultured with CD4⁺ T-cells to assess cytokine secretion, proliferation, and shifted Th17/Treg differentiation.

Both syngeneic and allogeneic grafts exhibited early IRI. By days 5-10, allografts developed AR with elevated liver enzymes and Banff scores. EGR1 rose transiently during IRI but re-escalated exclusively in allografts during AR, localizing to portal infiltrates. scRNA-seq showed preferential Egr1 expression in graft myeloid cells, while virtual knockout suggested immune-related regulatory effects. EGR1-associated APC activation and Th17-associated responses were observed in rejecting allografts. EGR1 overexpression in BMDCs promoted pro-inflammatory cytokine secretion, T-cell proliferation, and altered Th17/Treg-associated responses.

EGR1 contributes to liver allograft rejection by modulating myeloid APC responses and Th17/Treg-associated T-cell responses, highlighting its potential as a therapeutic target for AR.

Cardiovascular diseases (CVDs) remain a major cause of morbidity and mortality worldwide. Post-translational modifications (PTMs) are increasingly recognized as important regulators of cardiovascular pathophysiology, but how different PTMs interact in CVDs is still incompletely understood. This review focuses on the crosstalk between ubiquitination and other PTMs, including phosphorylation, SUMOylation, acetylation, methylation, O-GlcNAcylation, neddylation, and ADP-ribosylation/PARylation. We summarize representative cardiovascular mechanisms in which these modifications act competitively, cooperatively, or sequentially to influence protein stability, signaling, and function. We also discuss current limitations in establishing PTM interactions and highlight areas that require further investigation. A clearer understanding of these regulatory relationships may help identify disease-relevant PTM pathways and potential therapeutic targets in CVDs.

Closed-circuit rebreather (CCR) and helium-based breathing mixtures are widely used in technical diving. This study compared the effects of Heliox and Trimix on pulmonary function and decompression stress during CCR dives. Nineteen divers performed a standardized dive (50 ± 3 msw, 147 ± 10 min) using Heliox (16% O₂/84% He; n = 9) or Trimix (16% O₂/32% He/52% N₂; n = 10). Pre- and post-dive venous gas emboli (VGE), pulmonary function, lung ultrasound, heart rate variability, and inflammatory parameters were assessed. VGE were detected in all Heliox divers but in only 50% of Trimix divers. Heliox exhibited higher VGE counts 45 min post-dive than Trimix (12 [IQR 3-32] vs. 0 [IQR 0-6], p = 0.03); this difference disappeared by 90 min. No clinically significant pulmonary function changes were observed. Lung diffusion capacity decreased moderately regardless of breathing gas (-6% ± 7%). Lung ultrasound revealed minor transient B-line changes. Dive induced mild inflammatory responses, including neutrophilia and increased MRP8/14 in both groups. Heliox divers also showed transient complement activation alongside increased circulating platelets. CCR dives induced limited pulmonary stress, without gas-dependent differences. Although Heliox may promote a higher post-dive VGE burden and inflammatory responses, the relationship between these physiological effects and decompression sickness risk remains uncertain.

The number of people seeking gender-affirming medical care and gender-affirming hormone therapy (GAHT) is increasing. As sex steroids shape cardiometabolic physiology, GAHT is expected to meaningfully alter cardiometabolic risk. The aim of this review was to systematically determine and narratively synthesize evidence on the cardiometabolic effects of GAHT and identify clinically relevant knowledge gaps. We searched PubMed for English-language primary human studies published through November 26, 2025. Of 346 screened records, 96 unique original investigations were included. Most studies had less than 3 years of follow-up, the longest being 20 years in one electronic health record-based study. In transgender women, BMI was often reported as stable with higher fat and lower lean mass compared to baseline; insulin resistance tended to increase while fasting glucose and HbA1c were usually longitudinally stable. Lipid changes often showed reductions in total and low-density lipoprotein cholesterol as well as triglyceride levels. Blood pressure generally remained stable or decreased. In transgender women, VTE incidence was higher than in both cisgender women and men, whereas stroke and MI incidence was higher primarily in comparison with cisgender women. In transgender men, BMI was increased or stable and lean mass increased with variable fat mass changes and some long-term increases in visceral and liver fat. Glucose usually remained stable while insulin resistance findings were mixed. Lipid profiles commonly shifted toward lower high-density lipoprotein cholesterol and higher low-density lipoprotein cholesterol and triglycerides. Blood pressure findings were mixed with some cohorts showing an increase. In transgender men, MI incidence was higher than in cisgender women but generally not higher than in cisgender men; evidence for other cardiovascular outcomes was limited and inconsistent. Overall, evidence on systemic inflammation, renal and hepatic outcomes is sparse. In conclusion, GAHT is associated with quantifiable cardiometabolic changes, but magnitude and clinical relevance vary by regimen, population, baseline risk and study follow-up duration. Heterogeneous regimens, study methods, and confounding contribute to mixed findings. Major gaps persist with limited long-term prospective data, sparse mechanistic insights, underrepresentation of adolescents and non-European ancestry populations, and insufficient information on cardiometabolic outcomes with ageing.

Initially discovered and published in 2017, the heterozygous mutation (p.Arg52Leu) in the GNB2 gene is associated with sinus node dysfunction (SND) and atrioventricular block (AVB). Electrophysiological characterization using heterologous expression systems has demonstrated that this R52L GNB2 variant results in a larger G-protein-activated K⁺ (GIRK/I_{K, ACh}) current. So far, this has not been functionally validated in patient-derived disease modelling using human induced pluripotent stem cell-derived cardiomyocytes (CM).

Here, we differentiated CMs derived from human induced pluripotent stem cells (hiPSC-CMs) of a patient carrying the pathogenic p.Arg52Leu GNB2 variant (hiPSC^R52L-CMs) and compared electrophysiological properties with those of two unrelated healthy hiPSC-CMs control lines. Retinoic acid (RA) treatment during the differentiation was used to generate hiPSC-CMs with robust acetylcholine-activated K⁺ currents (I_{K, ACh}).

Patch-clamp experiments demonstrated that without GIRK channel stimulation the maximal diastolic potential (MDP) and spontaneous pacing rate did not differ between mutant and control cell lines and, moreover, a constitutively active I_{K, ACh} was not observed. Upon stimulation of GIRK channels with carbachol (CCh), hiPSC^R52L-CMs displayed an increased I_{K, ACh} density, a more hyperpolarized MDP and a slower spontaneous activity as compared to both control hiPSC-CMs cell lines, thus explaining the bradycardia reported from patients carrying the R52L GNB2 variant. Application of the specific I_{K, ACh} blocker XAF-1407 rescued the phenotype.

The reported, mutant GNB2 in patient-derived CMs is associated with a gain-of function upon GIRK channel stimulation and thereby a larger I_{K, ACh}, which could be potentially targeted and rescued by I_{K, ACh} blockers.

not applicable.

Dyslipidemia is a leading modifiable risk factor for cardiovascular disease (CVD), yet the shared genetic architecture of lipid traits remains poorly characterized, particularly in African-ancestry populations who bear a disproportionate CVD burden but are underrepresented in genomic research. We conducted multi-trait meta-analyses of genome-wide association summary statistics for HDL cholesterol, LDL cholesterol, triglycerides, and total cholesterol in 34 039 individuals of African ancestry, comprising 27 289 discovery participants from three continental African cohorts (ACCME, AWI-Gen, and UGR) and 6750 replication participants from the UK Biobank. Multi-trait analysis and eQTL colocalization across metabolic and cardiovascular tissues were then performed to identify shared genetic signals and characterize their tissue-specific regulatory mechanisms. Multi-trait analysis identified 90 genome-wide significant variants. Of these, 43 were novel variants with no prior exact-variant lipid association records. Eight variants across six genomic regions reached genome-wide significance in the multi-trait analysis and 70 of the 90 primary signals remained significant after total cholesterol was excluded. The strongest associations localized to established lipid loci including APOE/NECTIN2/TOMM40 (P = 8.09 × 10-133), CETP (P = 9.44 × 10-108), LIPC (P = 9.42 × 10-51), and LPL (P = 5.79 × 10-22), with 92% of signals replicating in the UK Biobank cohort. eQTL colocalization linked seven lead variants to tissue-specific gene expression and prioritized candidate regulatory genes. Together, these findings characterize shared lipid-associated signals with heterogeneous, trait-dependent effects in continental African populations and provide population-relevant evidence for candidate regulatory mechanisms.