Life

In this study, new improved inhibitors of the viral enzyme 3-chymotrypsin-like protease (3CL^pro) were designed using structure-based drug design techniques in an effort to discover more effective treatment of coronavirus disease 2019 (COVID-19). Three-dimensional models of 3CL^pro–inhibitor complexes were prepared by in situ modification of the crystal structure of the submicromolar covalent inhibitor IPCL6 for a set of 25 known inhibitors with published inhibitory potencies (${IC}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$). The QSAR model was prepared with a reasonable correlation between the calculated free energies of formation of the 3CL^pro-IPCL complex (∆∆G_com) and the experimentally determined activities ${IC}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$, which explained approximately 92% of the variation in the 3CL^pro inhibition data. A similar agreement was achieved for the QSAR pharmacophore model (PH4) built on the basis of the active conformations of the IPCL inhibitors bound at the active site of the 3CL^pro. The virtual combinatorial library of more than 567,000 IPCL analogues was screened in silico using the PH4 model and resulted in the identification of 39 promising analogues. The best inhibitors designed in this study show high predicted affinity for the 3CL^pro protease, as well as favourable predicted ADME properties. For the best new virtual inhibitor candidate IPCL 80-27-74-4, the inhibitory concentration ${IC}_{50}^{\mathrm{p}\mathrm{r}\mathrm{e}}$ was predicted equal to 0.8 nM, which represents a significant improvement in the inhibitory potency of known IPCLs. Ultimately, molecular dynamics simulations of the 12 newly designed top-scoring IPCL inhibitors demonstrated that the 3CL^pro–inhibitor complexes exhibited good structural stability, confirming the potential for further development of the designed IPCL analogues.

Knee osteoarthritis (KOA) and sarcopenia are prevalent age-related disorders that share common pathophysiological mechanisms such as aging, chronic inflammation, and physical inactivity. Their coexistence may aggravate functional decline and disability. This cross-sectional study aimed to compare the prevalence of sarcopenia between individuals with KOA and matched controls and to explore the relationship between femoral intercondylar cartilage (FIC) thickness and muscle-related parameters. A total of 228 participants (114 KOA, 114 controls) matched by age, sex, and body mass index were enrolled. Assessments included appendicular skeletal muscle mass index (ASMMI), handgrip strength, walking speed, and physical activity. In KOA patients, ultrasound measurements of FIC and quadriceps thickness and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were additionally obtained. Sarcopenia prevalence was higher in the KOA group than in controls (41.2% vs. 26.3%, p = 0.017). Greater FIC thickness was associated with higher ASMMI, stronger handgrip strength, faster walking speed, and lower WOMAC pain and total scores. These findings indicate that FIC thickness may serve as a potential structural biomarker linking cartilage integrity with muscle function in KOA.

Purpose: We aimed to present the clinical outcomes of a combined pharmacological and gas-assisted treatment for sub-macular haemorrhage secondary to neovascular age-related macular degeneration (nAMD). Methods: This retrospective case series included ten eyes with sub-macular haemorrhage (SMH) treated between January 2024 and September 2025. All patients received intravitreal alteplase (100 µg) and C₃F₈ gas, followed by aflibercept (2 mg or 8 mg) within a treat-and-extend regimen. BCVA- and OCT-based anatomical changes were recorded at baseline, 7–14 days, 1 month, 3 months, and 6 months. BCVA changes were analysed using repeated-measures testing. Results: Mean BCVA improved from 0.99 ± 0.21 logMAR at baseline to 0.89 ± 0.20 at 7–14 days, 0.80 ± 0.20 at 1 month, 0.60 ± 0.18 at 3 months, and 0.53 ± 0.20 at 6 months (p < 0.05 for overall change). Eight eyes (80 percent) showed restoration of foveal contour, while two developed foveal atrophy. No major adverse events occurred. Conclusion: Combined intravitreal alteplase and C₃F₈, followed by aflibercept, may provide favourable short-term visual and anatomical improvement in SMH secondary to nAMD. Early intervention appears beneficial, but larger controlled studies are needed to confirm these findings.