Search Results (1,087)

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. Full article

Usutu virus (USUV) is an emerging arbovirus recently associated with outbreaks in Western Europe. Although USUV is typically associated with asymptomatic or nonspecific febrile disease, the occurrence of severe neuroinvasive forms of disease has raised concern. There is currently no antiviral treatment available for USUV infection; therefore, we sought to investigate the protective effects of the nucleoside analogue 7DMA against USUV. Adding to 7DMA’s activity against USUV in vitro reported by us and others, we found that 7DMA inhibits USUV replication at multiple stages in mammalian cell lines Vero CCL81 and SH-SY5Y. In vivo testing of 7DMA using the susceptible IFNAR^-/- mouse model indicated that 7DMA treatment significantly reduced USUV viremia and viral load in tissues and prolonged mice survival. The characterization of the protective effects of 7DMA indicated that treatment also altered immunological aspects of disease development, further increasing the expression of mediators such as CXCL10, IL-15, and IFN-γ, and increasing neutrophil recruitment to target organs. We did not observe significant tissue damage or pathology in USUV-infected mouse brains, suggesting that systemic infection and disease are the major components leading to mortality in this model. We conclude that 7DMA exerts protective effects against USUV infection in the IFNAR^-/- model. Full article

Background/Objectives: The extent to which compression or inflammation contribute to the development of cervical radiculopathy and its associated symptoms remains unclear. This study aimed to evaluate whether herniated disc size correlates with baseline symptom severity and/or clinical outcome in patients with cervical radiculopathy, treated surgically or conservatively. Methods: This multi-centre retrospective cohort study included 206 patients with cervical radiculopathy due to a herniated disc. MRI scans from 108 patients in the NECK trial (surgical treatment, evaluating disc replacement) and 98 from the CASINO trial (surgical versus conservative treatment), were used to classify herniation size. Clinical outcome was assessed using the Visual Analogue Scale for arm and neck pain, the Neck Disability Index and the EuroQol VAS at baseline and one year after treatment. Binary logistic regression models were used to evaluate associations between herniation size and clinical outcome, adjusting for treatment type, gender, Body Mass Index and age. Results: A total of 107 patients presented with a small herniation, and 99 had a large herniation. Baseline mean NDI scores were 39.1 ± 15 (surgical group, n = 165) and 32.9 ± 16 (conservative group, n = 41). No association was observed between herniation size and clinical condition (OR 1.010, p = 0.323). After one year, mean NDI scores were 16.2 ± 15 (surgical group) versus 19.6 ± 22 (conservative group), with no significant associations between herniation size and outcome in either group. Similar findings were found for VAS arm and neck pain and EQ-VAS. Conclusions: Disc herniation size on baseline MRI showed no correlation with symptom severity or one-year clinical outcomes, suggesting that inflammatory mechanisms, rather than mechanical compression alone, play a key role in cervical radiculopathy. Full article

Background: We report UK findings from Music Interventions for Depression and Dementia in Elderly care (MIDDEL), a cross-national, clustered, randomised trial undertaken in 2018–2023 to evaluate the effectiveness of music interventions for depression symptoms in care home residents living with dementia (NCT03496675, clinicaltrials.gov (accessed on 1 December 2024)). The trial compared the effects of Group Music Therapy (GMT) with Recreational Choir Singing (RCS); GMT and RCS combined; and treatment as usual (TAU). Methods: In the intervention arms, the protocolized music interventions were delivered in care home units twice per week for three months, then once per week for three months. The primary outcome was depressive symptoms after six months, measured by MADRS. Secondary outcomes included well-being—EQ-5D-5L, Visual Analogue Scale (VAS); quality of life—QOL-AD; symptoms of dementia—SIB-8, NPI-Q; and caregiver distress—NPI-Q. The change in MADRS score from baseline to 6 months was assessed using a linear mixed-effects model. We report the multivariate model having both treatments as predictors, both unadjusted and adjusted, for the interaction between the treatments. Results: The UK trial started in 2022 after the pandemic lockdown, when 16 care home units were recruited and randomised, four per arm; 192 residents aged over 65 with depression and dementia participated. An ITT analysis of 146 participants retained at 6 months found neither intervention had a significant positive effect on any outcome. Significant unfavourable effects were found for RCS participants on MADRS, NPI symptom severity, and EQ-VAS. The combination of RCS + GMT had a detrimental effect on caregiver distress. Conclusions: MIDDEL UK findings do not support the use of GMT or RCS to alleviate depression in care home residents with dementia. Full article

Background: Atypical endometrial hyperplasia is a precursor of endometrial carcinoma, increasingly diagnosed in reproductive-aged women. Standard hysterectomy may constitute overtreatment. Fertility-sparing approaches, oral or local progestins, hysteroscopic resection, and combined regimens are widely used, though evidence largely derives from early-stage carcinoma. Methods: CENTRAL, EMBASE, Scopus, Web of Science, and PubMed were searched from inception to 13 April 2025. Eligible studies included premenopausal women with AEH treated with oral progestins, levonorgestrel intrauterine devices (LNG-IUDs), hysteroscopic resection, or combination regimens (e.g., oral progestins + metformin, LNG-IUD + GnRH analogues). Random-effects meta-analyses with multilevel modeling were applied. Risk of bias was assessed using RoB-2 and ROBINS-I; certainty of evidence was graded with GRADE-PRO. Results: Forty-nine studies (2313 women) were included. The pooled complete response (CR) rate was 85% (95% CI 80–89%). LNG-IUDs resulted in 88% CR and oral progestins in 80%. Combination therapies achieved up to 95% CR, though data were limited. Hysteroscopic resection combined with hormonal therapy reported high CR rates (96–97%) but relied on small, heterogeneous cohorts with uncertain reproducibility. The pooled recurrence rate was 19% (95% CI, 13–25%), lower with LNG-IUDs (14%) compared with oral progestins (22%). No response occurred in 14% overall and was lower with LNG-IUDs (13%) than oral progestins (19%). Among women attempting conception, the pooled pregnancy rate was 41%, and the live birth rate was 30%. The mean time to achieve CR was 5.6 months, whereas the mean time to recurrence was approximately 33 months. Conclusions: LNG-IUDs provide the most effective and well-supported fertility-sparing treatment for AEH, ensuring high remission with low recurrence. Despite favorable numerical outcomes, the evidence for hysteroscopic resection is limited and inconsistent, not supporting its routine use. Combination regimens may improve response but require confirmation in larger studies. Full article

Background: Prostacyclin (PGI₂), an abundantly produced bioactive lipid by oviductal epithelial cells, supports preimplantation embryo development by buffering oxidative stress. However, the mechanism linking PGI₂ signaling to embryonic redox control remains unclear. We investigated whether Iloprost (Ilo), a stable PGI₂ analogue, enhances preimplantation embryo development by alleviating oxidative stress via activation of the Nrf2/Keap1 pathway, and whether these effects depend on Nrf2 activity using the inhibitor brusatol. Methods: Porcine embryos were treated with Ilo to model oviductal PGI₂ signaling during in vitro culture. Developmental competence was evaluated by cleavage and blastocyst formation rates, and blastocyst quality by total cell number and TUNEL assays. Oxidative status was quantified by fluorescence detection of reactive oxygen species (ROS), and Nrf2 activation was assessed by nuclear localization and antioxidant-related gene expression. Results: Embryos treated with Ilo showed significantly increased blastocyst formation, reduced ROS, and upregulated antioxidant genes. Immunofluorescence confirmed increased nuclear translocation of Nrf2, indicating activation of the Nrf2/Keap1 signaling pathway. In contrast, embryos treated with brusatol showed reduced blastocyst formation, increased ROS, and downregulated antioxidant-related gene expression, whereas co-treatment with Ilo reversed these effects. Conclusions: This study demonstrates that PGI₂ protects embryos by activating Nrf2/Keap1 signaling, establishing this axis as a key antioxidant defense during embryonic development and highlighting its potential to improve embryo culture systems. Full article

The global shift to digital terrestrial television broadcasting (DTTB) from the conventional analogue has significantly transformed television culture, necessitating comprehensive technical and infrastructural evaluations. This study addresses the limitations of existing path-loss models for accurately predicting path loss in digital terrestrial television broadcasting in the UHF bands, motivated by the need for reliable, location-specific models that account for seasonal, meteorological, and topographical variations in Abeokuta, Nigeria. The study focuses on path-loss prediction in the UHF band using Ogun State Television (OGTV), Abeokuta, Nigeria, as the transmission source. Eight receiving sites, spaced 2 kilometers apart, were selected along a 16.7 km transmission contour. Daily measurements of received signal strength (RSS) and weather conditions were collected over one year. Seasonal path-loss models ${PL}_{wet}$ for the wet season and ${PL}_{dry}$. For the dry season, models were developed using multiple regression analysis and further optimized using least squares (LS) and gradient descent (GD) techniques, resulting in six refined models: ${PL}_{wet}$, ${PL}_{dry}$, ${PL}_{wet-LS}$, ${PL}_{dry-LS}$, ${PL}_{wet-GD}$, and ${PL}_{dry-GD}$. Model performance was evaluated using Mean Absolute Error, Root Mean Square Error, Coefficient of Correlation, and Coefficient of Multiple Determination. Results indicate that the Okumura model provided the closest approximation to measured RSS for all the receiving sites, while the Hata and COST-231 models were unsuitable. Among the developed models, ${PL}_{wet}$ ($RMSE- 1.2633$, $MAE - 0.9968$, $MSE - 1.5959$, $R - 0.9935$, $R^2 - 0.9871$) and ${PL}_{dry-LS}$($RMSE- 1.1884$, $MAE - 0.7692$, $MSE - 1.4124$, $R - 0.9942$, $R^2 - 0.9883$) were found to be the most suitable models for the wet and dry seasons, respectively. The major influence of location-based elevation and meteorological data on path-loss prediction over digital terrestrial television broadcasting communication lines in Ultra-High-Frequency bands was evident. Full article

Laser-induced periodic surface structures (LIPSSs) on silicon, generated by ultrashort pulsed lasers, provide an efficient means to tailor surface functionality. This work presents a multiphysics finite element study on the thermomechanical dynamics of silicon wafers irradiated by picosecond laser pulses, focusing on the melting regime where thermomechanical and hydrodynamic effects dominate. To illustrate the sequential nature of laser scanning, single-pulse irradiation models are developed as thermomechanical analogues of sequential laser irradiations. By positioning the laser focus near reflective boundaries and corners of the target, these models reproduce the stress wave interference that would occur between successive pulses in laser scanning. The results show that periodic surface structures are enhanced from mechanical standing wave interference within the molten layer, forming ripples with near-wavelength periodicity. The penetration depth (PD) is identified as a key factor controlling the duration and stability of these ripples: shallow PDs (75–150 nm) yield distinct, persistent patterns, while deeper PDs (~2.5 μm) lead to extended melting and hydrodynamic smoothing. Simulations of sequential laser pulse irradiations confirm that residual stresses and strains from the first pulse amplify deformation during the second, enhancing ripple amplitude and uniformity. Thus, the role of controlled excitation of mechanical standing waves governed by PD, boundary geometry, and pulse sequencing, in deterministic LIPSSs formation on silicon is revealed. Full article

Diroximel fumarate (DRF) is an orally administered prodrug used in multiple sclerosis (MS) treatment. Although it exhibits better gastrointestinal (GI) tolerability than its analogues, many patients still discontinue therapy due to frequent GI adverse events. To overcome these limitations, alternative drug delivery systems that bypass the GI tract are needed. Direct nose-to-brain delivery represents a promising approach to circumvent the blood–brain barrier and target the central nervous system; however, limited nasal mucosal absorption and the small volume of the nasal cavity pose significant challenges. Solid lipid nanoparticles (SLNs) can potentially overcome these obstacles by enhancing drug bioavailability and protecting against enzymatic degradation. This research aimed to develop an innovative intranasal nanoformulation of DRF to improve brain targeting and patient compliance. DRF-loaded SLNs were prepared using a solvent-diffusion technique with stearic acid as the lipid phase and Poloxamer 188 as the surfactant. The obtained nanoparticles displayed favorable technological characteristics, with a mean diameter of 210 nm, a polydispersity index of 0.17, and a zeta potential of −36 mV, suggesting good long-term stability. Interactions between SLNs and biomembrane models (MLV) were also studied to elucidate their cellular uptake mechanism. Future work will focus on evaluating the in vivo efficacy of this novel nanoformulation. Full article

Background: Meta-analyses on the prevalence and clinical significance of breast incidental uptake (BIU) at PET/CT are available only for [¹⁸F]FDG, showing that BIU is rare but malignant in a substantial proportion of cases. This study aimed to update the pooled prevalence and malignancy risk of BIU using different PET radiotracers, expanding [¹⁸F]FDG-based evidence. Methods: A comprehensive literature search of studies on BIU was carried out in two bibliographic databases, and the literature was screened up to 25 May 2025. Only original articles reporting BIU were selected. A proportion meta-analysis was conducted on a patient-based analysis using a random-effects model to estimate pooled prevalence, malignancy rate, and histological distribution. Results: In total, 29 studies were included in the systematic review and meta-analysis. PET/CT was performed using [¹⁸F]FDG (n = 25), radiolabeled somatostatin analogues (SSAs) (n = 3), or [¹⁸F]fluorocholine (n = 1). The pooled prevalence of BIU was 0.5% for [¹⁸F]FDG PET/CT, 3.4% for SSA PET/CT, and 2.6% for [¹⁸F]fluorocholine. The pooled malignancy rate among BIUs (female patients) was 33.5% for [¹⁸F]FDG, 86.4% for SSA, and 70% for [¹⁸F]fluorocholine PET/CT. Histological data were mainly available for [¹⁸F]FDG PET/CT, showing ductal carcinoma as the most frequent malignant histotype (pooled value 42.2%) and fibroadenoma (pooled value 14.8%) as the most frequent benign histotype. Conclusions: Similar to the case for [¹⁸F]FDG, BIU using other PET radiopharmaceuticals is uncommon but often malignant. Therefore, BIU should prompt dedicated breast imaging and, when indicated, histopathological confirmation. Further well-designed studies are needed to clarify the clinical impact of BIU detection and the prevalence and clinical significance of BIU using tracers other than [¹⁸F]FDG. Full article

The development of new antibiotics has been recognized for over two decades as a major challenge in combating multidrug-resistant bacteria. Herein, we report the synthesis and QSAR studies of claramine derivatives, a new class of broad-spectrum antimicrobial agents active against both susceptible and resistant Gram-positive and Gram-negative strains. The observed antimicrobial activities were rationalized based on key topological parameters of the derivatives, while cytotoxicity was interpreted by correlating half maximal inhibitory concentration (IC₅₀) values with QSAR models. Owing to the low cytotoxicity observed for several analogues, this molecular class represents a promising alternative for the development of novel agents to counteract multidrug resistance. Full article

Objectives: To compare the safety and efficacy of a prototype electronic heating device, Meiboleyes^®, with the BRUDER Moist Heat Eye Compress for the treatment of Meibomian Gland Dysfunction (MGD). Methods: Adults with evidence of active MGD (Ocular Surface Disease Index [OSDI] score ≥ 13, fluorescein tear break-up time [TBUT] < 10 s and meibomian gland secretion score ≤ 12 for 15 glands of the lower lid) were enrolled in this prospective, randomised, parallel group, investigator-masked dispensing study (Australian New Zealand Clinical Trials Registry–ACTRN12624000175572). Meibomian gland secretion (MGS) score and number of meibomian glands yielding liquid secretion (MGYLS), lipid layer thickness, TBUT, ocular physiology and subjective symptoms were measured at baseline, and 2 weeks and 6 weeks following treatment. Linear mixed model analysis was conducted to compare the two groups and changes over time. Results: Ten participants (average age 38.7 ± 14.5 years) in the Meiboleyes^® test group, and 10 participants (average age 38.9 ± 14.8 years) in the BRUDER control group completed the study. MGS and MGYLS significantly improved in both treatment groups from baseline to the 2-week and 6-week follow-up visits (p ≤ 0.006). Significant improvements in TBUT (5.5 ± 1.8 vs. 8.3 ± 2.1 s, p = 0.044), OSDI scores (45.2 ± 15.1 vs. 27.4 ± 12.9, p = 0.027) and visual analogue scale dryness (55.3 ± 27.2 vs. 28.0 ± 23.9, p = 0.023) were observed in the Meiboleyes^® group only after 6 weeks of treatment. No other significant differences were observed over time or between groups. Eight treatment-related adverse events were reported in the Meiboleyes^® group compared to seven in the BRUDER group. All resolved without sequalae. Conclusions: The prototype Meiboleyes^® device was safe and effective for use as an at-home treatment for MGD when used twice daily for six weeks. Improvements in meibomian gland function were comparable to the BRUDER Moist Heat Eye Compress, but significant improvements in tear film stability and subjective comfort after 6 weeks of treatment were observed in the Meiboleyes^® group only. Full article

A multimodal sensor was developed to record dissolved oxygen, L*a*b* colour, temperature, and pH. This work builds on an existing model that correlates blood oxygen saturation with L*a*b* colour values. An L*a*b* colour sensor was constructed from an RGB sensor and validated against a commercial colourimeter. Sensor performance was confirmed using reference colours. Dissolved oxygen was measured with a screen-printed electrode and an analogue-to-digital converter. The results highlight potential for future optical determination of oxygen saturation, combined with electrochemical measurement of oxygen partial pressure, and compensation for pH and temperature. Full article

Pyruvate:ferredoxin oxidoreductase (PFOR) is a key Achilles’ heel in anaerobic pathogens. We integrate electronic-structure calculations (DFT), cheminformatic QSAR metrics, and residue-resolved docking to distill a concise “recognition code” and translate it into practical design rules. Using nitazoxanide (Nita; ΔG_(bind) ≈ −10.0 kcal·mol⁻¹) as a well-established reference, productive binding requires a conserved triad: a hydrogen-bond donor addressing Thr-997 and Cys-840, a π–π stack with Phe-869, and a recurrent π–σ contact to Thr-997 that orients the scaffold. Deacetylation to tizoxanide unmasks the phenolic donor and raises local electrophilicity, yet it also slightly loosens pocket packing (−9.6 kcal·mol⁻¹). Strategic halogenation introduces a σ-hole interaction near Pro-29, tightening pose geometry without disrupting the donor network; the lead analogue yields −10.1 kcal·mol⁻¹, and two others match the reference by preserving the triad and hydrophobic belt. The result is a minimal, testable recipe—retain the phenolic donor, enforce Thr-997/Cys-840 and Phe-869, and add a calibrated halogen σ-hole—offering falsifiable predictions to surpass nitazoxanide and guiding synthesis and biophysical validation in targeted PFOR inhibition. Full article

Introduction: Apicectomy is an endodontic surgical procedure prescribed for persistent periapical pathologies when conventional root canal therapy or retreatment have failed. Accurate intraoperative visualization of the root apex and surrounding structures remains challenging and subject to possible errors. Augmented reality (AR) allows for the addition of real-time digital overlays of the anatomical region, thus potentially improving surgical precision and reducing invasiveness. The purpose of this pilot study is to describe the application of an AR method in cases requiring apicectomy. Materials and Methods: Patients presenting with chronic persistent apical radio-translucency associated with pain underwent AR-assisted apicectomy. Cone-beam computed tomography (CBCT) scans were obtained preoperatively for segmentation of the target root apex and adjacent anatomical structures. A custom visual–inertial odometry (VIO) algorithm was used to map and stabilize the segmented digital 3D models on a portable device in real time, enabling an overlay of digital guides onto the operative field. The duration of preoperative procedures, was recorded. Postoperative pain measured by a Visual Analogue Scale (VAS), and periapical healing assessed with radiographic evaluations, were recorded at baseline (T0) and at 6 weeks and 6 months (T1–T2) after surgery. Results: AR-assisted apicectomies were successfully performed in all three patients without intraoperative complications. The digital overlap procedure required an average of [1.49 ± 0.34] minutes. VAS scores decreased significantly from T0 to T2, and patients showed radiographic evidence of progressive periapical healing. No patient reported persistent discomfort at follow-up. Conclusion: This preliminary pilot study indicates that AR-assisted apicectomy is feasible and may improve intraoperative visualization with low additional surgical time. Future larger-scale studies with control groups are needed to validate the method proposed and to quantify the outcomes. Clinical Significance: By integrating real-time digital images of bony structures and root morphology, AR guidance during apicectomy may offer enhanced precision for apical resection and may decrease the risk of iatrogenic damage. The use of a visual–inertial odometry-based AR method is a novel technique that demonstrated promising results in terms of VAS and final outcomes, especially in anatomically challenging cases in this preliminary pilot study. Full article