Vesicoureteral reflux (VUR) may lead to reflux nephropathy and end-stage kidney disease (ESKD). Whether ESKD due to primary VUR identifies kidney transplant recipients at higher long-term graft risk remains incompletely defined, particularly when VUR phenotype, bladder status, reconstructive history, and infection burden are not captured. We performed a retrospective 1:3 case-control study of kidney transplant recipients with ESKD attributed to primary VUR and non-VUR controls transplanted at a tertiary center. Patients whose primary ESKD etiology was bladder exstrophy, epispadias, posterior urethral valves, neurogenic bladder, prior cystectomy, complex congenital lower urinary tract anomalies, or myelomeningocele were not included in the primary VUR cohort. The dataset captured age at ESKD, VUR grade and laterality, dominant renal involvement, native ureteral reimplantation, native nephrectomy, clean intermittent catheterization, bladder augmentation, urinary reconstruction, and UTI episodes during the 12 months before and after transplantation. The primary endpoint was death-censored graft failure. The cohort included 32 primary VUR recipients and 96 controls. Median age at ESKD among VUR recipients was 31 years (IQR 22.8-39.0), and median age at transplantation was 39 years (IQR 30-46). VUR grade was IV in 9/32 recipients (28.1%) and V in 23/32 recipients (71.9%); VUR was bilateral in 22/32 (68.8%). Native ureteral reimplantation/UCNA was recorded in 25/32 (78.1%), native nephrectomy in 13/32 (40.6%), clean intermittent catheterization in 12/32 (37.5%), and bladder augmentation in 6/32 (18.8%). UTI burden decreased from 48 episodes during the 12 months before transplantation to 15 episodes during the 12 months after transplantation; recurrent UTI decreased from 15/32 (46.9%) to 1/32 (3.1%). Post-transplant cystographic evaluation was not routine; graft VUR was documented in no patient. Graft failure occurred in 14/32 VUR recipients (43.8%) and 46/96 controls (47.9%). Estimated 10 year death-censored graft survival was 66.8% in the VUR group and 65.3% in controls (log-rank p = 0.977). VUR was not associated with graft failure in the crude Cox model (HR 1.01, 95% CI 0.55-1.84; p = 0.978) or in an exploratory adjusted model (HR 0.88, 95% CI 0.48-1.62; p = 0.677). In this single-center cohort, ESKD due to primary VUR was not associated with inferior death-censored kidney graft survival. These phenotype data indicate that the prognostic question in VUR is not the diagnostic label alone, but the combination of reflux severity, bladder/reconstructive status, native urinary tract management, and infection burden.
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.
Older adults with metastatic triple-negative breast cancer (mTNBC) remain underrepresented in clinical trials. Although sacituzumab govitecan (SG) improved outcomes in the phase III ASCENT trial, real-world data in older populations are limited. We conducted a retrospective multinational study across 18 oncology centers in Central Europe, including patients with mTNBC treated with SG between August 2021 and May 2025. Patients were stratified by age at SG initiation: <65 versus ≥65 years. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), treatment modifications and safety. Among 303 patients, 76 (25.1%) were aged ≥65 years. Older patients had more comorbidities, more prior palliative treatment lines and more frequent ECOG performance status ≥1. In unadjusted analyses, patients aged ≥65 years had longer median OS (12.8 vs. 10.9 months; HR 0.70, 95% CI 0.49-0.99; p = 0.045) and PFS (5.4 vs. 4.1 months; HR 0.73, 95% CI 0.54-0.97; p = 0.031). ORR, DCR, treatment modifications and grade ≥3 neutropenia were comparable between groups. In multivariable analyses, age was not independently associated with OS or PFS. In this selected real-world cohort, patients aged ≥65 years receiving SG had outcomes at least comparable to younger patients, without apparent excess severe toxicity. Survival differences were likely influenced by baseline disease characteristics and patient selection rather than chronological age itself.
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.
Persistent chemical warfare agents (CWAs), designed for deposition as liquid droplets or coarse aerosols, pose prolonged environmental and forensic risks due to their persistence on contaminated surfaces. Roofing materials represent large, exposed areas in urban environments and may act as important reservoirs of CWAs following a release. However, their role in controlling contaminant fate and forensic detectability remains poorly understood. In this study, the behavior of four persistent CWAs - A-230, A-234 (Novichoks), cyclosarin (GF), and sulfur mustard (HD) - was investigated on five representative roofing materials differing in composition. Extraction efficiency, long-term persistence, and the divergence between matrix-retained and surface-accessible contamination were systematically evaluated using comparative bulk extraction and wipe sampling approaches. Dissipation half-lives, degradation-product formation, and long-term forensic detectability were assessed using gas chromatography-mass spectrometry. Results showed strong matrix-dependent behavior. A-series agents exhibited the highest persistence, particularly in porous cement-based materials. Wipe sampling consistently recovered only a fraction of the deposited mass and declined faster than bulk extraction, indicating rapid migration of agents into the matrix interior. Transformation products remained detectable in all materials after 90 days, even when parent compounds were substantially depleted. These findings demonstrate that roofing materials represent significant but often neglected reservoirs controlling the long-term retention, transformation, and forensic detectability of persistent CWAs. The results highlight the need to extend current decontamination and risk-assessment paradigms to include such surfaces and emphasize the importance of matrix-adapted sampling and analytical strategies in urban contamination scenarios.
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.
Social deficits following maternal immune activation (MIA) are widely used to model the impact of prenatal inflammation on autism spectrum disorder (ASD). Since the immune response to polyinosinic:polycytidylic acid (poly(I:C)) depends on its molecular weight, we hypothesized that poly(I:C) molecular composition shapes the emergence of social deficits in offspring. Pregnant Wistar rats received a single subcutaneous injection of low- or high-molecular-weight poly(I:C) (LMW or HMW; 10 mg/kg) on gestational day 14. Offspring of both sexes were assessed for social behavior in early life and adulthood using the homing response and social interaction tests, respectively. Open field and elevated plus maze tasks controlled for locomotor activity and anxiety-like behavior. Data were analyzed using nested linear mixed models accounting for litter and cohort effects. HMW, but not LMW, poly(I:C) significantly impaired neonatal homing responses, indicating early disruption of maternal affiliation. In adulthood, HMW-exposed offspring of both sexes showed reduced social investigation, with males additionally exhibiting increased social approach. Furthermore, both HMW- and LMW-exposed males displayed hyperlocomotion and increased time in the centre of the open field, without accompanying changes in anxiety-like behavior. In summary, although both HMW- and LMW-exposed offspring showed alterations in basal activity, only HMW poly(I:C) produced robust deficits in early social communication and adult social behavior. These findings identify molecular weight as a key determinant of MIA model outcomes and support HMW poly(I:C) as the more reliable and translationally valid preparation for modeling ASD-associated prenatal immune challenges.
Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment for metastatic renal cell carcinoma (mRCC). Nivolumab monotherapy remains an established option in previously treated patients; however, real-world data (RWD) from Central and Eastern Europe are limited. We conducted a retrospective multicenter cohort study using data from the RENIS II registry, including 501 patients with mRCC treated with nivolumab in the second or later line between 2013 and 2025 across the Czech Republic and Slovakia. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), safety, and exploratory analyses of baseline inflammatory indices (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], and systemic immune-inflammation index [SII]). Median OS was 24.2 months and median PFS was 8.6 months. The ORR was 28.8% and the DCR was 61.2% in the response-evaluable population. Grade 3/4 adverse events were recorded in 11.4% of patients. In exploratory analyses, higher baseline NLR, PLR, and SII were associated with inferior survival in univariable analyses. In multivariable models, NLR and PLR remained independently associated with OS and PFS, whereas SII did not retain independent prognostic significance. In this large multicenter real-world cohort, nivolumab monotherapy demonstrated consistent clinical activity and manageable toxicity in previously treated mRCC, with outcomes comparable to those reported in clinical trials and other European real-world studies. Baseline inflammatory indices, particularly NLR and PLR, showed potential prognostic value and warrant further investigation.
Garden nasturtium (Tropaeolum majus L.) is a rich source of bioactive compounds, particularly glucotropaeolin, and is increasingly used in functional foods. Maintaining glucosinolate stability during processing is critical for ensuring consistent bioactivity. This study systematically investigated the kinetics and mechanism of glucotropaeolin degradation in edible extracts obtained from seeds, leaves, and flower buds under typical processing and storage conditions. Glucotropaeolin hydrolysis was primarily driven by myrosinase, producing benzyl isothiocyanate, which then degraded to form benzyl thiocarbamate and 1,3-dibenzyl-2-thiourea. Untreated or lyophilised extracts showed rapid glucotropaeolin degradation, whereas boiling-induced myrosinase inactivation substantially improved glucotropaeolin stability. Additionally, an analysis of commercial garden nasturtium extracts revealed surprisingly low levels of glucotropaeolin and benzyl isothiocyanate, highlighting the impact of industrial processing. These findings provide insight into the mechanism of glucotropaeolin stability and highlight processing strategies for preserving bioactive glucosinolates, supporting the development of functional foods with predictable bioactive profiles.
All animals age. However, aging is a heterogeneous process, and individual organisms age differently. Moreover, within the same organism, cells or organs do not age at the same speed. For instance, neurodegeneration, a hallmark of aging, generally manifests later than other peripheral aging signs. The genetic determinants of aging are not completely understood. Gain-of-function (GoF) mutations in leucine-rich repeat kinase 2 (LRRK2GoF) are major genetic risk factors for Parkinson's disease (PD). By analyzing PD patients and LRRK2GoF mice, we show that PD represents an accelerated aging disorder driven by STING-dependent inflammation. This inflammation begins peripherally, disrupts the blood-brain barrier, and causes dopaminergic neurodegeneration. Mechanistically, aging or LRRK2GoF causes endolysosomal decline, resulting in cytosolic self-DNA accumulation and the release of DNA-containing extracellular vesicles (EVs) that activate the cGAS-STING pathway within and between cells. Our findings identify LRRK2GoF as a key driver of accelerated aging and systemic inflammaging through DNA-containing EVs, highlighting potential therapeutic targets to counteract inflammaging and neurodegeneration.
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.
Pistacia lentiscus L. (PLL) is traditionally used in Sardinian folk medicine for osteoarthritis (OA) and represents a source of polyphenols with potential antioxidant and anti-inflammatory activity. To investigate the phenolic profile, the antioxidant potency, the total phenolic content, cytotoxicity, and anti-inflammatory properties of an aqueous leaf extract of PLL to explore its possible relevance in OA. Total phenolic content was assessed by the Folin-Ciocalteu spectrophotometric method. The polyphenols were also characterized by a High-Performance Liquid Chromatography (HPLC). The antioxidant ability was assessed by the 2,2-diphenyl-1-picrylhydrazyl (DPPH). The anti-inflammatory activity was examined through COX-1 and COX-2 inhibition while, the cytotoxicity was evaluated in dysplastic oral keratinocytes (DOK), human gingival fibroblasts (HGnF), and human periodontal ligament fibroblasts (HPLF) by using the WST-1 and the xCELLigence assays. The total phenolic content was 249.78 ± 37.10 mg GAE/g DW, where myricetin glycoside and catechin were the most abundant compounds. The DPPH scavenging capacity showed an IC50 value 32.22 ± 6.43 μg/mL indicating considerable antioxidant potential of the extract. At 10 μg/mL the extract inhibited COX-1 and COX-2 by 92.07% and 71.04%, respectively, with IC50 values of 5.14 μg/mL and 13.87 μg/mL. No relevant cytotoxicity was observed at lower concentrations in the tested cell lines. PLL extract shows high total phenolic content, which together with the DPPH document strong antioxidant potency of the compound. This data together with the marked anti-inflammatory activity, and the limited cytotoxicity, support the potential interest of PLL extract as a natural candidate to counteract OA manifestations.
Zinc oxide (ZnO) is a prominent semiconductor for photocatalysis; however, its efficiency is often hampered by the rapid recombination of photogenerated electron-hole pairs. To mitigate this limitation, we designed a surface engineering approach based on the functionalization of hydrothermally synthesized ZnO nanoparticles with the protic ionic liquid triethylammonium propanesulfonate tetrafluoroborate ([TEA-PS][BF4]) at different loadings (2.5-10 wt%). X-ray diffraction (XRD) analysis confirmed the formation of wurtzite ZnO with nanometric crystallite sizes (26-47 nm), indicating that the ionic liquid (IL) influenced nucleation and crystal growth by acting as a capping agent during synthesis. Scanning electron microscopy (SEM) and Fourier-transform infrared spectroscopy (FTIR) results confirmed successful surface modification and revealed IL-induced morphological changes. Photocatalytic activity was assessed via methylene blue (MB) degradation under ultraviolet (UV) light, with the optimization of catalyst mass and pH. The best performance was achieved using 40 mg of catalyst under alkaline conditions (pH 10). Under these conditions, pristine ZnO degraded 71.7% of MB after 120 min, while the ionic-liquid-modified samples reached 89.6%. The sample containing 5.0 wt% ionic liquid (Z-IL5) showed the highest efficiency, attributed to enhanced adsorption and increased accessible surface area. Density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations were performed on IL-adsorbed ZnO clusters. The computed interaction energies and non-covalent interaction (NCI) analyses confirmed the strong interfacial anchoring of the IL, while excited-state and frontier molecular orbital descriptors indicated electronic effects consistent with improved charge separation. Finally, ionic liquid functionalization is an effective surface engineering strategy for improving the photocatalytic activity of ZnO, with interfacial effects likely contributing to reduced charge losses and enhanced degradation kinetics in aqueous media.
We report primary analysis results from the Phase 3 PERSPECTIVE study comparing ibrutinib + rituximab versus placebo + rituximab in patients with previously untreated follicular lymphoma requiring treatment per Groupe d'Etude des Lymphomes Folliculaires criteria who were ineligible for chemoimmunotherapy due to age and/or comorbidities. The primary endpoint was investigator-assessed progression-free survival (PFS). Patients were randomly assigned 3:1 to receive ibrutinib (560 mg) or placebo once daily until progression, together with rituximab 375 mg/m2 weekly for 4 weeks, then every 8 weeks for 12 cycles. Overall, 445 patients were assigned to receive ibrutinib + rituximab (n = 334) or placebo + rituximab (n = 111). With a median follow-up of 53.7 months, PFS was significantly improved with ibrutinib + rituximab versus placebo + rituximab (hazard ratio, 0.713 [95% CI, 0.532-0.955]; P = 0.0231; median 42.0 vs. 32.8 months), as was overall response rate (81% vs. 68%; rate ratio, 1.190 [95% CI, 1.039-1.364]; P = 0.004). Complete response rates also favored ibrutinib + rituximab (31% vs. 26%). Overall survival (OS) was immature and not significantly different between arms (hazard ratio 1.121 [95% CI, 0.771-1.631]; P = 0.5485). Grade ≥3 adverse events occurred in 78% versus 57% of patients with ibrutinib + rituximab versus placebo + rituximab, most commonly neutropenia (16% vs. 7%), pneumonia (9% vs. 5%), hypertension (8% vs. 5%), COVID-19 (6% vs. 2%), COVID-19 pneumonia (6% vs. 3%), and diarrhea (6% vs. 2%). In patients with previously untreated follicular lymphoma, adding ibrutinib to rituximab significantly improved PFS and response rates but did not improve OS. This trial was registered at www.clinicaltrials.gov, NCT02947347.
Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare, molecularly defined subgroup of non-clear cell RCC (nccRCC) lacking an approved standard treatment. We report the exploratory analysis of this entity within the SUNNIFORECAST trial. SUNNIFORECAST evaluated ipilimumab/nivolumab versus standard of care (SOC) in previously untreated, advanced nccRCC. The primary endpoint was the 12-months overall survival (OS) rate. Secondary endpoints included median OS, progression free survival (PFS) and overall response rate (ORR). PD-L1 expression was assessed exploratorily. Of 309 randomized patients, 30 had centrally confirmed FH-deficient RCC (ipilimumab/nivolumab, n=14; SOC, n= 16). The 12-months OS rate was 85.7% (95% confidence interval [CI] 53.9-96.2%) versus 73.3% (95% CI 43.6-89.1%), median OS was 35.7 months (95% CI 16.8 months-NE) versus 24.7 months (95% CI 10.6-37.7 months, hazard ratio [HR] 0.46 [0.17-1.20]), and ORR 42.9% versus 33.3%, favoring ipilimumab/nivolumab. Twenty-four patients were evaluable for PD-L1 expression; 21 had a combined positive score (CPS) ≥1. In this subgroup, the 12-months OS rate was 80.0% (95% CI 40.9-94.6%) versus 72.7% (95% CI 37.1-90.3%), median OS 38.3 months (95% CI 8.8 months-NE) versus 24.7 months (95% CI 8.8 months-NE, HR 0.43 [0.14-1.34]) and ORR 40.0% versus 36.4% for ipilimumab/nivolumab versus SOC, respectively. Exploratory analyses suggest trends toward improved 12-months OS-rate, median OS and ORR with ipilimumab/nivolumab versus SOC in FH-deficient RCC. The majority of tumors demonstrated PD-L1-expression (e.g. CPS ≥ 1), warranting further investigation in prospective studies.
To report the approach, technical success, safety, and short-term outcomes of thoracic duct stenting for treating chylothorax and chylous ascites in a patient with Yellow Nail Syndrome. A 57-year-old male with Yellow Nail Syndrome, characterized by yellow thickened nails, lymphedema, and respiratory abnormalities, required repeated thoracocenteses for chylothorax. A thoracic duct intervention involving percutaneous transluminal angioplasty and balloon-expandable stent implantation via retrograde access was performed. Procedure characteristics, clinical success, complications, and follow-up were recorded. Thoracic duct stenting was a safe and technically successful procedure. After the procedure, the patient was relieved of symptoms. This technique could be considered for patients with recurrent chylothorax and chylous ascites, including those with Yellow Nail Syndrome. Further research is required to validate these findings.
Morocco, encompassing both Mediterranean and Saharan regions, is recognized as a biodiversity hotspot, hosting a rich fauna of wild bees. While taxonomic research on Moroccan bees has accelerated in recent years, an update was needed to provide a more complete taxonomic foundation. Here, we present an updated checklist of Moroccan wild bees since the first complete checklist published in 2020. This work summarises and proposes a total of 143 changes to the previous checklist, which correspond to 14.8% of taxa compared to the first checklist: two new genera for the country (Schmiedeknechtia and Aglaoapis), 36 species recently described as new to science, 37 species recently recorded in Morocco, and 16 species newly reported here for the country. We further document 18 published synonymies, 33 taxonomic acts and clarifications, and provide records for 28 species previously lacking precise data. We also exclude 14 species from the previous checklist and 25 names based on published synonymies and taxonomic acts and clarifications. This update brings the total to 1,043 wild bee species belonging to six families and 70 genera, compared to 961 species in the 2020 checklist, with 10% (108 species) currently considered as endemic to Morocco. This first update, resulting from a collaborative effort among experts, strengthens the taxonomic framework required to advance research on wild bee diversity, endemism, and conservation in Morocco.
This study evaluated and compared the marginal fit of CAD-CAM zirconia crown copings with and without a 3D-printed control model. This prospective in vitro trial involved 30 zirconia crown copings made from the same STL file. These were divided into two groups. Half of them had their own 3D-printed control model made from the same STL file (With-Printed-Model group), whereas the other half lacked any control model (No-Printed-Model group). Both groups underwent manual adjustments in a systematic way. Their marginal gaps were evaluated using a digital optical microscope from eight zones: buccal, mesiobuccal, mesial, mesiopalatal, palatal, distopalatal, distal, and distobuccal. The mean values with standard deviations for the With-Printed-Model and No-Printed-Model groups were 15.18 ± 14.49 and 12.46 ± 14.09 µm, respectively. All crown copings from both groups were below 75 µm. Statistical analysis showed a significant difference between the two groups. The No-Printed-Model group demonstrated superior marginal fit compared to the With-Printed-Model group. However, the largest marginal gaps from each group were still within the clinically acceptable range below 75 µm. Although the 3D-printed control model did not improve marginal fit, its primary function is to effectively identify major manufacturing errors.
A series of pyrazinamide-derived 1,2,3-triazoles featuring systematic chlorination of the pyrazine ring and diverse aryl substituents was synthesized and evaluated for antimycobacterial activity. Biological activity screening revealed broad-spectrum antimycobacterial activity and good selectivity toward mycobacteria over other pathogens, with 11 of the prepared compounds showing activity against Mycobacterium tuberculosis (Mtb) H37Ra and/or Mtb H37Rv (MIC ≤62.5 μg/mL). Structure-activity relationship analysis showed that 5-Cl substitution on the pyrazine ring was associated with improved antimycobacterial activity, with the best MIC values observed for compound 7 against Mtb H37Ra (MIC = 1.98 μg/mL) and compound 37 against Mtb H37Rv (MIC = 1.56 μg/mL). The tested compounds retained activity against drug-resistant Mtb isolates and partially against naturally resistant Mycobacterium abscessus, while showing low in vitro cytotoxicity in the HepG2 cell line and favorable selectivity indices. During advanced cytotoxicity testing, both compounds 7 and 37 displayed substantially lower hemolytic activity than bedaquiline, indicating a favorable erythrocyte safety profile within the tested concentration ranges. In vivo toxicity testing on Galleria mellonella showed low acute toxicity for both compounds. Mechanistic studies on compounds 7, 27, 31, and 37 revealed reduced biosynthesis of fatty acids and derived lipids, a phenotype consistent with interference with the Fatty Acid Synthase I (FAS I) system.
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.