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Rural general practitioners (GPs) play a vital role in providing healthcare to populations in remote areas, yet there is a significant shortage of doctors willing to work in these regions. Despite the critical need, a strong preference for urban practices persists among young GPs in Europe, exacerbating the lack of healthcare providers in rural settings. Understanding the motivation factors influencing young GPs' decisions to work in rural areas is essential to address this workforce distribution problem. This study aims to identify the main motivating factors that drive young GPs to work in rural areas across four European countries. Additionally, the study seeks to propose strategies to enhance recruitment of young GPs in rural healthcare settings. A key informant survey was conducted across four member countries of the European Rural and Isolated Practitioners Association (EURIPA). The EURIPA Motivating young EuropeAn DOctors for rural Work (MEADOW) study utilized a semi-structured questionnaire. The survey targeted young GPs in Denmark, Norway, Turkey, and the Czech Republic, collecting data from 350 respondents. Our survey revealed that 64.14% of young GPs expressed an interest in rural practice, with major motivating factors including accessibility of schooling for their children, income profitability, and employment opportunities for partners. The study highlights that financial incentives alone are insufficient to motivate young GPs to work in rural areas. Instead, a comprehensive approach that includes improving rural medical education, ensuring access to quality schools for children, and providing employment opportunities for partners is crucial. Addressing these multifaceted needs can enhance rural recruitment and retention efforts across Europe.

Craniosynostosis is a congenital disorder characterized by premature fusion of one or more cranial sutures, resulting in abnormal skull growth and, in some cases, elevated intracranial pressure. Accurate assessment of cranial morphology is essential for diagnosis, surgical planning, and evaluation of postoperative outcomes. Three-dimensional computed tomography allows detailed visualization of cranial shape; however, measurements may be influenced by external forces during image acquisition, such as contact between the occipital region and the supporting surface. It remains unclear whether such forces produce measurable deformation in infants with immature, not fully ossified skulls. In this study, preoperative and postoperative cranial CT scans were used to generate patient-specific 3D virtual models. Models were registered using anatomical landmarks in the orbital and nasal regions to standardize orientation. Surface difference analysis quantified regional morphological changes. Finite element modeling was employed to simulate cranial deformation under two loading conditions: intracranial pressure and external load representing the weight of the head in supine position. Displacement patterns were analyzed and compared to assess the relative impact of each loading condition. Results demonstrated that the most pronounced postoperative changes occurred in the parietal region, corresponding to surgical osteotomy lines, with mean displacement of 7.3 ± 3.6 mm. The frontal region remained stable, while the occipital region showed slight inward displacement (-4.6 ± 2.7 mm). FEM simulations revealed minimal deformation under external loading alone (maximum 0.09 mm), whereas intracranial pressure produced substantially larger, symmetric displacement, with maximum parietal displacement reaching 12.1 mm. Combined loading closely resembled intracranial pressure alone. The maximal deformation induced by external contact during CT scanning was more than two orders of magnitude smaller than that generated by intracranial pressure. These findings indicate that external forces during CT acquisition have negligible impact on cranial morphology measurements in pediatric patients, and observed postoperative changes primarily reflect true anatomical alterations. FEM provides a robust framework to quantify biomechanical effects and distinguish imaging artifacts from genuine morphological changes, supporting the reliability of CT-based assessment for clinical decision-making and surgical evaluation in craniosynostosis.

Venetoclax-rituximab (VR) following covalent Bruton tyrosine kinase (BTK) inhibitor therapy is the fixed-duration standard of care for patients with chronic lymphocytic leukaemia (including small lymphocytic lymphoma). Pirtobrutinib, a non-covalent BTK inhibitor, is approved for use after treatment with a covalent BTK inhibitor as a continuous therapy option. We aimed to evaluate the addition of pirtobrutinib to VR as a fixed-duration regimen in patients with relapsed or refractory chronic lymphocytic leukaemia. This open-label, multicentre, randomised, controlled, phase 3 trial was conducted at 152 sites (comprising community hospitals and academic centres) across 22 countries. Eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic lymphocytic leukaemia (including small lymphocytic lymphoma), and had previously been treated with at least one line of therapy that could include a covalent BTK inhibitor. Patients who had previously received a non-covalent BTK inhibitor, venetoclax, or another BCL2 inhibitor were not eligible. Enrolled patients were randomly assigned (1:1) using an interactive web-based randomisation system, stratified by del(17p) status and previous exposure to covalent BTK inhibitors, and assigned to receive either pirtobrutinib plus VR (PVR) or VR. Both groups received oral venetoclax (25 cycles) and intravenous rituximab (six cycles); the PVR group also received oral pirtobrutinib for 28 cycles, with a three-cycle pirtobrutinib-rituximab lead-in before venetoclax initiation. For this prespecified interim analysis, the primary endpoint was progression-free survival in the intention-to-treat population, assessed by a masked independent review committee (IRC) as per 2018 International Workshop on Chronic Lymphocytic Leukemia guidelines. Safety analyses were conducted in the safety population, defined as all randomly assigned patients who took at least one dose of any study treatment. All analyses were based on a data cutoff date of Feb 2, 2026. The trial is registered at ClinicalTrials.gov, NCT04965493, and is ongoing but no longer recruiting. Between Oct 13, 2021, and Oct 28, 2024, 784 patients were screened, of whom 639 were randomly assigned: 321 to the PVR group and 318 to the VR group. The median age of patients was 68·0 years (IQR 60·0-74·0), of whom 439 (69%) were male and 200 (31%) were female. The median number of previous therapies was 2 (IQR 1-3); 510 (80%) of 639 patients had previous exposure to covalent BTK inhibitors, of whom 362 (71%) discontinued their most recent drug of this class owing to progressive disease. At a median follow-up of 27·3 months (IQR 19·5-38·7), PVR showed a significant improvement in IRC-assessed progression-free survival compared with VR (hazard ratio 0·547 [95% CI 0·400-0·748]; p=0·0001). The median 24-month progression-free survival rate was 87% (95% CI 82·3-90·4) in the PVR group versus 72% (65·7-77·0) in the VR group, and the median progression-free survival was not reached (IQR 31·7-not estimable) in the PVR group versus 39·7 months (21·5-50·0) in the VR group. This benefit was consistent across prespecified subgroups, including patients with previous exposure to covalent BTK inhibitors. The most frequent treatment-emergent adverse event of any grade in both groups was diarrhoea, reported in 106 (34%) of 316 patients in the PVR group and 110 (35%) of 311 patients in the VR group. The frequency of treatment-emergent adverse events of grade 3 or higher was similar in both groups (249 [79%] of 316 patients in the PVR group vs 227 [73%] of 311 patients in the VR group); the rate of tumour lysis syndrome of grade 3 or higher was lower in the PVR group (1%; three of 316) than in the VR group (4%; 12 of 311). Rates of atrial fibrillation or flutter of any grade were low (11 [3%] of 316 patients in the PVR group vs eight [3%] of 311 patients in the VR group). Rates of treatment discontinuation owing to treatment-emergent adverse events deemed as related to any of the study drugs were similar: 5% (17 of 316 patients) in the PVR group versus 5% (16 of 311 patients) in the VR group. There were five treatment-related deaths: one in the PVR group and four in the VR group. In patients with previously treated chronic lymphocytic leukaemia, PVR showed significant improvement in progression-free survival compared with VR, with consistent results in patients who had previously received covalent BTK inhibitors and no new safety signals. To our knowledge, these results represent the first randomised phase 3 evidence comparing a novel fixed-duration regimen to the current standard of VR in relapsed or refractory chronic lymphocytic leukaemia, supporting PVR as a potential new standard of care. Eli Lilly and Company.

The development of bioactive peptides derived from food is crucial for alleviating nonalcoholic fatty liver disease. As a traditional meat product, Jinhua ham is rich in various bioactive peptides and has anti-inflammatory and liver-protective effects. This study aims to isolate novel dual-function peptides with anti-inflammatory and hepatoprotective properties from Jinhua ham hydrolysates. Potential target peptides were identified through mass spectrometry and computational virtual screening, followed by molecular docking and molecular dynamics simulations. In vitro, 1 mg/mL of NWRPPQPIK (NW-9) reduced AST, ALT, IL-1β, IL-6, and TNF-α levels by 51.66%, 54.08%, 24.66%, 33.71%, and 15.79%, respectively. In vivo, NW-9 also demonstrated therapeutic effects. This is because NW-9 can alleviate liver inflammatory damage caused by the cGAS-STING pathway. These findings provide a theoretical basis for the development of Jinhua ham-derived dual-function peptides with anti-inflammatory and hepatoprotective properties in the functional food industry, further expanding the high-value utilization of food-derived bioactive peptides.

Patients with classic Hodgkin lymphoma (cHL) with primary refractory disease, early relapse, or extranodal disease have a higher risk of relapse after salvage therapy and autologous stem cell transplant (ASCT). Post-ASCT brentuximab vedotin (BV) maintenance improved progression-free survival (PFS) in high-risk relapsed/refractory (R/R) cHL in the AETHERA trial, but subgroup analysis suggested that the benefit in patients transplanted in complete metabolic response (CMR) is unclear. In a large international real-world cohort, we assessed the efficacy of BV maintenance stratified by pre-ASCT metabolic response and by the number of clinical risk factors as defined in the AETHERA trial. Adult patients with R/R cHL who met AETHERA risk criteria were included. Utilizing propensity score analyses, PFS and OS were assessed overall and in subgroups of CMR (442 pts) and partial metabolic response (PMR, 249 pts). We observed that post-ASCT BV maintenance was associated with significantly higher PFS in the subgroup with PMR (5-year PFS: 59.6% vs 43.3% HR = 0.52, CI95: 0.33-0.82; p = 0.007). In the subgroup of patients with CMR, BV maintenance did not significantly improve PFS (5-year PFS: 75.8% vs 62.3% HR = 0.88, CI95: 0.59-1.32; p = 0.29). However, when focusing on patients with CMR treated post-FDA approval of BV, there was a significant PFS benefit observed in those treated with BV maintenance vs. not (5-year PFS: 81.2% vs 55.2% HR = 0.40, CI95: 0.22-0.72; p = 0.003). Overall, BV maintenance after ASCT remains an important therapy for high-risk R/R cHL patients, especially for those in PMR or those in CMR.

A series of novel chiral urea and thiourea compounds were designed as multitarget-directed ligands for Alzheimer's disease and evaluated against hAChE, hBChE, and hMAO-B, with exploratory assessment of HSD10. These chiral compounds were synthesized and fully characterized, and their enantiopurity was confirmed via HPLC. Biological screening revealed that several of the 38 single-enantiomer derivatives exhibited potent triple inhibition of hAChE, hBChE, and hMAO-B. Biological screening revealed that a significant number of the 38 synthesized single-enantiomer urea and thiourea derivatives potent inhibition across the primary target panel. Among them, compounds 14S (hAChE: 0.08 μM, hBChE: 0.93 μM, hMAO-B: 0.02 μM), 23R (hAChE: 0.06 μM, hBChE: 0.74 μM, hMAO-B: 0.08 μM), 6S (hAChE: 0.08 μM, hBChE: 0.65 μM, hMAO-B: 0.08 μM), and 30S (hAChE: 0.04 μM, hBChE: 0.74 μM, hMAO-B: 0.19 μM) showed the most promising multitarget profiles. Compounds 6S and 23R also displayed anti-Aβ aggregation activity, whereas 12S combined dual hMAO-B/hAChE inhibition with antioxidant activity. Compounds 3R and 11R were found to be highly active against hMAO-B (0.03 μM and 0.06 μM, respectively) and hBChE (0.68 and 0.72 μM). HSD10 inhibition was limited overall, with only compound 26S showing moderate activity (52.2%) at higher micromolar concentration. Molecular docking and molecular dynamics simulations supported the proposed ligand-target interactions for the most active compounds. In addition, selected derivatives showed no acute cytotoxicity under the tested conditions in HepG2 cells and high permeability potential in the PAMPA-BBB assay. Based on their in vitro profiles, seven compounds (3R, 6S, 11R, 12S, 14S, 23R, and 30S) were advanced to in vivo evaluation, and compounds 6S, 12S, and 23R, 30S produced significant improvements in the Morris Water Maze model. Collectively, these findings identify chiral urea and thiourea derivatives as promising lead structures for further anti-Alzheimer drug discovery.

Chronic inflammation is a prolonged immune response that leads to the development of numerous diseases, including arthritis, cardiovascular disorders, and metabolic syndromes. Currently, synthetic anti-inflammatory medications are widely used to treat chronic inflammation due to their high efficacy. However, their long-term use is often associated with serious side effects. This led to an urgent need to explore the anti-inflammatory drugs that are more efficient and exhibit few or no adverse effects. Several studies have revealed the anti-inflammatory properties of various plants. However, most focus primarily on listing anti-inflammatory plants and their phytoconstituents, with limited scientific validation. In addition, no compiled data is available that includes comprehensive pre-clinical and clinically validated studies of anti-inflammatory plants and their phytoconstituents. The current study aims to provide a comprehensive overview of chronic inflammation and its management, addressing the challenges of synthetic anti-inflammatory medications, and investigating the potential of plants and their phytoconstituents as anti-inflammatory agents, with scientific validation through preclinical and clinical studies. Literature was searched, analyzed, and compiled from PubMed, ScienceDirect, and Google Scholar databases. The search terms used included anti-inflammatory plants, phytoconstituents, in-vitro and in-vivo, anti-inflammatory drugs, inflammation mechanism, etc., and several combinations of these keywords. A total of 297 publications published between August 1978 and February 2026 were included in this review. Overall, this review provides a detailed mechanistic explanation of plant-derived anti-inflammatory drugs for the treatment of chronic inflammation.

This study systematically maps murine in vivo research on small-molecule radiation medical countermeasures (RMCs) published between 2014 and 2024, with quantitative survival analysis focused on whole or total-body irradiation (WBI/TBI) models relevant to hematopoietic acute radiation syndrome (H-ARS). Murine models are central to radiation biology because they provide controlled, reproducible systems for studying radiation injury, testing candidate therapeutics, and generating preclinical evidence relevant to clinical translation. A structured PubMed search identified 5,558 records, of which 258 studies met inclusion criteria. Study characteristics and outcomes were extracted, and survival studies were filtered for (WBI/TBI), appropriate dose range, Kaplan-Meier reporting, and data integrity. To reduce heterogeneity, meta-analysis was restricted to C57BL/6 mice exposed to 7.5-9.5 Gy WBI. Of 118 survival studies, 48 cohorts were eligible, but only the 8.0-8.5 Gy and 8.5-9.0 Gy dose ranges supported quantitative synthesis. Using restricted mean survival time (RMST; τ = 30 days), pooled analysis showed survival gains of 12 and 13 days, respectively, in treated versus control cohorts. Multiple chemically distinct RMCs improved survival, with the largest effects observed for delta-tocotrienol derivatives. These findings highlight both the translational value of murine models and the need for greater standardization in experimental design and reporting.

To evaluate the association between bevacizumab use and fistula occurrence in patients with metastatic or persistent cervical cancer (CC) treated with definitive chemoradiotherapy (CRT). We retrospectively analyzed 101 patients with FIGO stage IIB-IVB CC treated with curative-intent CRT between 2017 and 2023. The primary outcome was the incidence of fistula formation, with a focus on the impact of bevacizumab exposure. Fistulas occurred in 7 of 101 patients (6.9%). Among the 13 patients treated with bevacizumab, 4 (30.8%) developed fistulas compared with 3 (3.4%) of 88 not receiving bevacizumab. Univariable analysis showed significant associations with bevacizumab use (OR = 12.59, 95% CI: 2.43-65.38, p = 0.003), and FIGO stage IVB (OR = 21.90, p = 0.001). In multivariable analysis, bevacizumab (AOR = 13.5, 95% CI: 1.84-99.5, p = 0.011) and FIGO stage IV (AOR = 26.7, 95% CI: 2.59-274.4, p = 0.006) remained independent predictors. No fistulas occurred after 2021, coinciding with institutional discontinuation of bevacizumab in metastatic or persistent disease after CRT (p = 0.043). Bevacizumab use and FIGO stage IV disease were associated with increased risk of fistula formation after definitive CRT. These findings highlight the need for careful treatment planning when considering bevacizumab in previously irradiated patients, particularly in the current era of multimodal therapy.

This study assessed perceptions of health and science students and academic staff regarding the health risks, environmental impact, and regulation of dental amalgam (DA). As DA faces increasing restrictions, understanding the views of students and academic staff is essential for evaluating educational and policy readiness. A cross-sectional survey was distributed to 1,230 participants in the Czech Republic. The questionnaire explored awareness of mercury exposure from DA, health and environmental concerns, and familiarity with regulations. Responses were statistically compared across disciplines. Overall, 35.8% of respondents did not recognize DA as a mercury source, and 48.5% did not view it as a health risk. Most did not consider DA an occupational hazard for dental professionals. However, 55.3% saw it as an environmental pollutant. While 59.2% supported restricting DA use in pregnant women and 51.0% in children, only 22.0% supported a complete ban. Most respondents preferred composites for aesthetic reasons (88.5%) rather than health concerns. Dental students differed significantly from other groups in several key areas, particularly regarding perceived health risks and support for restrictions on dental amalgam use. Perceptions of dental amalgam differed according to educational background. While most participants supported restricting its use in vulnerable populations, dental students were less likely to perceive it as a significant health risk and were less supportive of a complete ban. These findings highlight the importance of evidence-based education and public health communication regarding dental amalgam and mercury-related issues.

Circadian rhythm and oxidative stress are fundamental biological regulators whose intricate interplay plays a pivotal role in cancer progression and immunosuppression. These two factors engage in a bidirectional, self-reinforcing pathological loop that drives tumor progression and fosters an immunosuppressive tumor microenvironment. In the context of cancer, circadian rhythm disruption promotes immunosuppression by reducing cytotoxic CD8+ T cell infiltration while expanding populations of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells. Oxidative stress acts as a pivotal effector with dual roles, it promotes immunosuppression by polarizing macrophages toward an M2 phenotype, yet it is also strategically harnessed to disrupt immunosuppressive networks. Critically, oxidative stress serves as a central link, wherein circadian rhythm disruption, through the accumulation of ROS, drives the recruitment of immunosuppressive cells and upregulates immune checkpoints such as PD-L1, thereby suppressing anti-tumor immunity. Furthermore, emerging evidence highlights the potential of circadian rhythm as a prognostic biomarker and underscores the promise of chrono-immunotherapy, which strategically times interventions to align with the circadian rhythm to optimize anti-tumor immune function. Collectively, the circadian rhythm and redox balance represent novel therapeutic targets, with pharmacological agents that restore circadian rhythm and enable cell-selective modulation of oxidative stress. Thus, integrating circadian rhythm and oxidative stress into oncology offers a promising strategy to improve cancer prevention, prognosis, and treatment outcomes.

The management of locally-advanced, resectable head and neck squamous cell carcinoma (HNSCC) is undergoing a major shift driven by the integration of neoadjuvant immunotherapy (nIO). The rationale for nIO lies in its administration within an immunologically active, treatment-naïve microenvironment that enhances immune priming and anti-tumor response. Despite encouraging clinical data, including the pivotal KEYNOTE-689 trial and multiple phase II studies, methodological heterogeneity in trial design, endpoint definitions, and response criteria currently hampers data comparability and the establishment of new standards of care. This expert narrative review proposes a structured framework for standardizing clinical, pathologic, imaging, and translational endpoints in HNSCC nIO trials, highlighting harmonized definitions of pathologic response, practical reporting templates, and methods to evaluate immune priming. Standardization of response evaluation, biomarker integration, and trial methodology is essential to accelerate the translation of neoadjuvant immunotherapy into routine clinical practice for HNSCC.

This contribution provides a detailed mechanistic insight into a remarkably complex reaction of neutral 1-Ph-2-tert-butyl-1H-1,2-benzazaborole (1) with elemental potassium in THF, yielding the known 10π-aromatic 1H-2,1-benzazaborolyl (2,1-Bab-) potassium salt (2), an isoelectronic species with indenyl potassium, along with a racemic mixture of a new potassium hydridoborate complex (3), formed together with 2 in ca. 1 : 1 molar ratio. Unlike derivatives of isoelectronic 1H-indene, which undergo various self-protonation processes under analogous conditions, for 1, we propose a completely different and rather complex, non-linear tandem mechanism. Key species are four enantiomeric pairs of short-lived, dimeric, diamagnetic intermediates, denoted α, β, ω1 and ω2, possessing structures related to Gomberg's dimer and Krause's adduct. Based on an exhaustive multinuclear NMR analysis of the reaction mixture, including experiments with C3-methylene deuterium-labelled starting compound 1-dn (n ∈ {0-2}) and the observation of a primary AKIE (kH/kD ≫ 1), as well as a detailed analysis of full scan mass spectra and observed ions in ultrahigh-resolution LDI-MS data of the resulting mixture of isotopologues of the final product 3-dn (n ∈ {0-4}), comprising multiple isotopomers, in combination with probabilistic calculations, electrochemical studies, and DFT calculations, we were able to reconstruct the full sequence of reaction steps and pathways. The presented results support the involvement of various H-atom transfer (HAT) processes within pairs of radical-anionic species K+1˙-, proceeding through different transition states, and, most notably, reveal an extremely rare boron-targeted HAT. These findings provide a basis for developing synthetic routes to unconventional boron hydrides.

Glioblastoma (GBM) is a highly aggressive brain tumor with limited prognostic markers to predict patient outcomes reliably. This study investigates the perioperative levels of tryptophan, kynurenine, and neopterin in patients with GBM to assess their potential as biomarkers for prognosis. Twenty-four patients with supratentorial GBM and 24 age- and gender-matched healthy controls were included. Blood and urine samples were collected at four time points: preoperatively, three days postoperatively, prior to adjuvant therapy, and post-adjuvant therapy. Analytical measurements of tryptophan, kynurenine, and neopterin levels were conducted using liquid chromatography-tandem mass spectrometry, and statistical analyses were performed to determine their correlation with survival outcomes. The analysis revealed significant perioperative fluctuations in neopterin, kynurenine and tryptophan levels in GBM patients. Moreover, a trend (p = 0.08) of an association between preoperatively obtained blood level of kynurenine and survival probability was observed supporting further validation of kynurenine-pathway biomarkers in larger, molecularly annotated cohorts.

Traditional endpoints in acute ischaemic stroke trials, most commonly the mRS, incompletely capture the full spectrum of patient outcomes. The win ratio (WR) is a hierarchically structured composite outcome measure that prioritises endpoints according to clinical importance. In this study, we applied win statistics to investigate which components drive the overall treatment effect. Of 253 patients in the TENSION (Efficacy and safety of ThrombEctomy iN Stroke with extended leSION and extended time window) trial, 125 were randomised to EVT + BMT and 128 to BMT alone. Endpoints were ranked hierarchically: (1) time to death, (2) mRS at 12 months, (3) occurrence of any serious adverse event and (4) EuroQOL 5-dimension scores at 12 months. Outcomes were analysed using win statistics. The overall WR was 1.61 (95% CI, 1.19-2.18; P = .002), indicating a relative frequency of wins for EVT + BMT of approximately 60% among untied pairwise comparisons. The win difference was 22.8% (95% CI, 8.3%-36.3%; P = .002), of which 15.7% were attributable to survival. Win ratios were consistent across prespecified subgroups, including both sexes, age ≤ 80 years, baseline mRS 0-1, conscious patients, ASPECTS 5 and M1 occlusions. The WR provides an informative complement to conventional mRS-based analyses in acute ischaemic stroke trials. Our hierarchical composite outcome analysis demonstrated how ordering of hierarchical components affects the resulting estimates, with the predominant treatment effect in TENSION being driven by improved survival. These findings support the complementary use of hierarchical composite outcomes in future neurointerventional trials.

The rising wave of antimicrobial resistant organisms, together with the lack of novel group of antibacterial agents, represents a major concern in modern medicine. This study aims to investigate the anti-staphylococcal potential of two semi-synthetic derivatives of naturally occurring nitrogen-containing molecules (1 nm and 2 nm). The two semi-synthetic analogues were evaluated against reference bacterial strains and clinical bacterial isolates. Furthermore, the most active compound, 1 nm, was subjected to synergistic activity screening with the commercial antibiotics against MRSA. The toxicity profile of 1 nm was further explored using in vitro (HepG2 and HK-2 cells) and in vivo (Galleria mellonella) models, accompanied by an insight into its in silico physicochemical characteristics and cytotoxicity. Our results suggest that this derivative possesses promising activity against clinically relevant staphylococci, while showing a favourable safety and bioavailability profile. In addition, this compound showed synergistic or additive effects in combination with several clinically important antibiotics. 1 nm demonstrates promising adjuvant anti-staphylococcal activity, with a favourable safety profile and an additive interaction with the last-resort antibiotic linezolid, supporting its potential to mitigate resistance development within combination strategies.

Endoglin (ENG) is expressed in liver sinusoidal endothelial cells (LSECs), where it regulates endothelial activation and inflammation. The 7-ketocholesterol (7-K), a cholesterol oxidation product, accumulates in the liver and induces endothelial dysfunction. ENG has been shown to play an important role in adhesion processes in other endothelial models but its role in LSECs upon 7-K exposure remains unclear. We hypothesized that 7-K treatment of LSECs would confirm the critical role of ENG in endothelial activation, potentially outweighing the contributions of the cell adhesion molecules VCAM-1 and ICAM-1. Human LSECs were exposed to 25 µM 7-K. Protein expression and monocyte adhesion were assessed by flow cytometry, and soluble ENG was measured by ELISA. 7-K reduced ENG expression, while ICAM-1 was markedly upregulated. 7-K increased monocyte adhesion to LSECs, which was abrogated by ICAM-1, but not by ENG neutralization. We showed that 7-K promotes a pro-inflammatory phenotype defined by ICAM-1, rather than ENG. Thus, we propose that individual roles of ENG, ICAM-1, and VCAM-1 must be carefully considered when studying endothelial dysfunction.

Gangliosides are structurally complex glycosphingolipids that regulate cellular signaling via interactions with extracellular binding partners and by influencing protein function within the membrane. Their comprehensive analysis remains analytically challenging, in part due to low endogenous abundance, extensive structural diversity, and the frequent occurrence of isomeric species arising from both glycan and ceramide moieties. Here, we present a hydrophilic interaction liquid chromatography (HILIC) nanoelectrospray ionization tandem mass spectrometry (nanoESI-MS/MS) method specifically designed to achieve isomer-resolved analysis and molecular species-level quantification of gangliosides. To improve characterization of low-abundance fatty acyl fragments, the workflow was extended by combining nanoESI with online fraction collection and subsequent direct infusion. The method demonstrated stable chromatographic performance, high sensitivity, and reproducible quantitative results across ten mouse tissues. Application of the workflow enabled quantification of 80 ganglioside molecular species belonging to 18 subclasses and revealed pronounced tissue-specific differences in subclass distribution and ceramide composition. Overall, this study establishes a robust and sensitive platform for comprehensive ganglioside analysis, providing new opportunities to investigate ganglioside diversity, regulation, and function in complex biological systems.

Severe asthma affects a minority of patients with asthma; however, it substantially impacts morbidity, health-care use, and systemic corticosteroid-related harm. Despite the increasing use of biological treatments, achievement of severe asthma remission remains elusive. Notably, real-world data on the disease burden and remission potential of severe asthma in Europe remain limited. We aimed to close this knowledge gap, offering insights with global relevance. Using data from 13 455 adults with severe asthma enrolled in the European Severe Heterogeneous Asthma Registry, Patient-centred Clinical Research Collaboration (SHARP CRC), this cross-sectional observational study evaluated the burden of severe asthma and remission-related clinical domains (exacerbations, asthma control, airflow limitation, and maintenance oral corticosteroid use) across Europe and examined their relationship with disease duration, biological therapy, and type 2 biomarkers (blood eosinophils, fractional exhaled nitric oxide [FeNO], and total IgE). Patients with severe asthma had been enrolled in national registries according to local principles and guidelines and in accordance with the European Respiratory Society/American Thoracic Society guidelines; 3% (430 of 13 885) of patients were excluded due to no consent for the international study and/or missing medication data. Patients were predominantly female (59%; 7999 of 13 453), with adult-onset asthma (82%; 8751 of 10 711), and a median disease duration of 23 years (95% CI 20-26 years). 59% (4148 of 7006) of patients had FEV1/FVC of 0·7 or less, 62% (4680 of 7568) had FEV1 lower than 80% predicted, and 89% (3519 of 3968) had at least one active disease domain. Despite 79% (10 632 of 13 453) receiving biological therapy, more than 66% (2621 of 3968) still had at least two active domains. Elevation of type 2 biomarkers persisted (89% [2806 of 3153] with at least one elevated biomarker) despite widespread biological and maintenance oral corticosteroid treatment. A subset of biologic-naive patients (35%; 1069 of 3018) exhibited a rapid accumulation of disease burden within less than 10 years, suggesting a potentially accelerated progression trajectory. This pan-European analysis of severe asthma revealed significant clinical heterogeneity and a substantial disease burden despite advanced therapies, highlighting the enduring nature of type 2 inflammation, the potential inadequacy of current remission strategies with available therapeutic approaches, and the necessity for early identification of high-risk patients. SHARP Clinical Research Collaboration and consortium partners: European Respiratory Society, GlaxoSmithKline Research and Development, Chiesi Farmaceutici Società per Azioni, Novartis Pharma Aktiengesellschaft, Sanofi-Genzyme Corporation, and Teva Branded Pharmaceutical Products R&D.