Minimally invasive surgery (MIS) for hallux valgus (HAV) correction may benefit from using the medial eminence to enhance lateral capital fragment translation. This study investigates whether osteotomy placement through the medial eminence correlates with improved HAV and forefoot width (FW) correction. A retrospective analysis of 20 patients who underwent MIS bunion correction was performed. Pre- and postoperative radiographs were reviewed to assess hallux valgus angle (HVA), intermetatarsal angle (IMA), distal metatarsal articular angle (DMAA), sesamoid position, osteotomy location, osteotomy angle, capital fragment shift, and forefoot width. Pearson correlation and multivariable linear regression were used to identify associations. Chart review was performed at the one-year mark for complications (recurrence, infection, non-union, hardware failure). Significant correlations were found between DMAA and HVA (r = 0.883, p < 0.001), DMAA and IMA (r = 0.573, p = 0.008), and HVA and capital fragment shift (r = 0.541, p = 0.014). Osteotomy location and angle were not significantly associated with correction. Multivariable analysis showed DMAA was independently associated with HVA correction (β = 0.679, p < 0.001), and both capital fragment shift and metatarsal head angulation were associated with FW narrowing. Additionally, no patients in this cohort experienced complications. Use of the medial eminence in MIS osteotomy was not associated with improved HAV or FW correction. Angular deformity parameters and lateral fragment shift were more predictive of radiographic outcomes.
This review highlights that integrating physiological, molecular, imaging, and AI-based approaches enables early and reliable detection of graft incompatibility, improving rootstock-scion selection, orchard sustainability, fruit productivity, and long-term tree performance. One of the most serious problems in fruit growing is the breaking, weakening, or dying of the tree at the graft union, either within a short period of time or after 10-15 years. This condition is often triggered by environmental factors; however, it is certainly not solely caused by environmental conditions. This problem is defined as graft incompatibility. Graft incompatibility refers to the failure of successful anatomical and physiological integration between a rootstock and a scion, primarily due to biochemical, molecular, and genetic mismatches that impair vascular reconnection and long-term stability of the graft union. Graft incompatibility remains a significant constraint in fruit tree production, resulting in reduced longevity, yield, and quality of orchards. This review integrates recent advancements in physiological, molecular, and technological approaches for the early detection of graft incompatibility, with special emphasis on Prunus species such as sweet cherry. Physiological and biochemical markers, including phenolic accumulation, antioxidant enzyme activities, and isozyme patterns, serve as early indicators of incompatibility. At the molecular level, transcriptomic, metabolomic, and epigenetic analyses have revealed differentially expressed genes (DEGs) and post-translational modifications associated with stress signaling, vascular reconnection, and callus formation. Imaging-based non-destructive technologies such as micro-CT, MRI, terahertz, and hyperspectral imaging now allow real-time visualization of graft-union structures without damaging plant tissues. The integration of artificial intelligence and machine learning with multi-omics datasets and imaging tools offers unprecedented potential for predictive diagnosis and compatibility assessment. Collectively, these multidisciplinary advances are reshaping the detection and management of graft incompatibility, enabling faster, more reliable, and sustainable rootstock-scion selection in fruit tree breeding.
Controlling bacterial contamination on pig carcasses is critical for meat safety and public health within the One Health framework. Salmonella and Listeria monocytogenes are major foodborne pathogens associated with pork products. This study evaluated the decontamination efficacy of chitosan (0.2% and 0.5%) compared to lactic acid (2% and 5%) and citric acid (2% and 5%) against Salmonella Typhimurium and L. monocytogenes inoculated on pig skin surfaces, while also assessing effects on spoilage microbiota (mesophilic bacteria, psychrotrophic bacteria, and Enterobacteriaceae). The goal was to identify sustainable, natural alternatives to conventional organic acid treatments for early-stage carcass interventions in slaughterhouses. Pig skin samples (25 cm²) were collected from commercial carcasses, inoculated with approximately 5-6 log colony-forming units per square centimeter of the target pathogens or left non-inoculated, and treated by spraying with the respective solutions. Samples were stored at 7 °C for 48 h. Microbial enumeration followed International Organization for Standardization methods for mesophiles (Plate Count Agar, 30 °C/72 h), psychrotrophs (Plate Count Agar, 7 °C/10 days), Enterobacteriaceae (Violet Red Bile Glucose agar), Salmonella (Xylose Lysine Deoxycholate agar), and L. monocytogenes (Oxford agar). Data were analyzed using one-way analysis of variance and Tukey honestly significant difference test (p < 0.05). Organic acids provided modest initial reductions (<1 log) in spoilage organisms and mainly bacteriostatic effects against pathogens. Chitosan at 0.5% achieved the strongest reductions, lowering initial mesophilic and psychrotrophic counts by >1 log and maintaining the lowest L. monocytogenes levels (only +0.44 log increase over 48 h vs. >2 log in controls). For Salmonella, 0.5% chitosan produced a progressive 1.46-log reduction over 48 h (final counts 2.68 log lower than the control), demonstrating bactericidal activity, unlike the bacteriostatic profile of organic acids. Chitosan, particularly at 0.5%, exhibited superior, more sustained antimicrobial efficacy against both pathogens and spoilage microbiota on pig skin compared with lactic and citric acids. These findings highlight chitosan as a promising natural, sustainable decontamination agent for pig carcasses, with the potential to enhance compliance with European Union microbiological criteria and support greener meat-processing strategies. Further commercial-scale validation and combination approaches are recommended.
In accordance with Article 12 of Regulation (EC) No 396/2005, EFSA has reviewed the maximum residue levels (MRLs) currently established at European level for the pesticide active substance clofentezine. Although this active substance is no longer authorised within the European Union, codex maximum residue limits (CXLs) were established by the Codex Alimentarius Commission and import tolerances were reported by Member States and the UK (including the supporting residues data). Based on the available data, EFSA assessed the CXLs and the import tolerances reported, and a consumer risk assessment was carried out. Although no risk to consumers was identified, all CXLs and import tolerances were found to be supported by inadequate data. Hence, the consumer risk assessment is considered indicative only and further consideration by risk managers is needed.
In the context of the research on food ingredients, "novel microorganisms (NMs)" refers to microorganisms without a documented history of safe consumption. The utilization of these novel microorganism-derived ingredients is expanding rapidly within the food and nutrition sectors, and such ingredients are broadly classified into three categories, live microorganisms, non-viable bacteria, and purified metabolites, each characterized by distinct risk profiles and unique regulatory requirements. Despite their growing prevalence, a globally harmonized protocol for safety assessment is currently lacking, leading individual nations to implement disparate safety frameworks within their respective regulatory systems. Consequently, this review aimed to provide a scientific foundation for the standardization of safety criteria by performing a comparative analysis of established guidelines from the European Union (EFSA), United States (FDA), Canada (Health Canada), Brazil (ANVISA), Thailand (Thai FDA), India (FSSAI), Japan (FSCJ), and Australia/New Zealand (FSANZ). Our analysis identified several universal safety parameters for live NMs, including hemolytic activity, antimicrobial resistance (AMR), toxigenic potential, the production of antimicrobial substances, metabolic profiling, and toxicological assessment. While toxicological evaluation, the production of antimicrobial substances, and the absence of live NMs were the consensus criteria for the safety evaluation of non-viable bacteria and purified microbial metabolites, an allergenicity evaluation is additionally required for purified microbial metabolites. Based on our analysis, this review proposed safety standards for novel microbial food ingredients including live microorganisms, non-viable bacteria, and purified metabolites by synthesizing these diverse regulatory landscapes.
The aim of the article was to analyse the trends in oncology interventional clinical trials in the United Kingdom (UK) from 2000 to 2025, compare with major global regions, and to assess the potential impact of the New UK Clinical Trials Regulation (UK CTR) 2026 regulatory reform on the future competitiveness. Retrospective observational analysis of interventional oncology trials registered on ClinicalTrials.gov with comparison across the UK, European Union (EU; comprising 27 member states), the United States, and the Republic of China (China). Number of trials, phase distribution, funding source, and population-adjusted trial density across three time intervals (2000-2015, 2016-2020, 2021-2025). The UK experienced growth in oncology trials until 2017, followed by declines associated with Brexit and the COVID-19 pandemic, and partial recovery thereafter. While the EU and USA maintained high absolute trial numbers, both showed declining population-adjusted research intensity over time. China demonstrated the fastest growth, with substantial increases in early phase trials and trial density. Despite recent challenges, the UK retains strong infrastructure and expertise in oncology research; the 2026 regulatory reform may support the future attractiveness of the UK, particularly for early phase trials, although increasing global competition remains a significant issue.
To identify demographic, organisational and psychological predictors of nursing care rationing among nurses working in Polish healthcare settings and to examine its associations with burnout, coping strategies and depressive symptoms. A cross-sectional study. The study was conducted between February and September 2025 among 434 nurses employed in various healthcare settings in Poland. Data were collected using the Basel Extent of Rationing of Nursing Care-Revised (BERNCA-R), the Maslach Burnout Inventory (MBI), the Mini-COPE and the Beck Depression Inventory (BDI). Descriptive statistics and univariate and multivariable linear regression analyses were performed. This study adhered to the STROBE guidelines for cross-sectional studies. The mean BERNCA-R score indicated moderate levels of care rationing. In the multivariable model, higher care rationing was associated with shift work, higher patient loads, employment in professional unions and higher income levels. Living in medium-sized cities was associated with lower rationing levels. Additionally, the coping strategy 'turning to religion' showed a small but significant positive association with care rationing. The most frequently rationed activities included patient conversations, emotional support, patient education, proper documentation and shift handovers. Nursing care rationing is influenced by organisational and workforce-related factors. Workload and shift organisation emerged as key modifiable determinants. Addressing these may reduce care rationing and improve care quality and safety. Rationing is strongly influenced by modifiable organisational factors, including staffing and shift organisation. High patient loads and shift work increase the risk of missed care, particularly in communication, documentation and patient support. Optimising staffing and work organisation may enhance patient safety. This study highlights organisational drivers of missed care in a Central European context and provides evidence to inform staffing strategies and healthcare policy. None.
Background: Sickness absenteeism has long been an organizational problem due to the consequent loss of productivity (1-2% of gross domestic product in European Union countries) and job overload for workers. We designed and conducted an observational cohort study to describe and analyze the short sickness events and their derived absence days in a large university tertiary hospital, also incorporating the fit for work assessment and the anti-influenza vaccination coverage. Materials and Methods: The anonymous data of workers with at least one day of certified presence during the period 1 January-31 August 2025 were extracted from the hospital information system. Crude and job-specific absence rates were calculated. The incidence rate ratios (IRRs) along with their 99% confidence intervals for the covariates were obtained by a negative binomial model fit. Results: The overall sickness event rate was 0.54 per 100 person-workdays, ranging from 0.22 (physicians) to 0.92 (technical/administrative staff), while the overall sickness day rate was 0.88 per 100 person-workdays, spanning from 0.31 (physicians) to 1.41 (health and social care assistants). The multi-variable model fit of sickness days returned significant IRRs for being vaccinated (0.74; 99% CI: 0.58-0.93), for male gender (0.77; 99% CI: 0.63-0.95) and for limitations regarding the fitness for work assessment (2.14; 99% CI: 1.51-3.05). Conclusions: Our findings indicate that, in a large tertiary university hospital, an anti-influenza vaccination campaign may effectively protect workers from sickness absences, even accounting for gender, age and regardless of job typology and fit for work assessment. Furthermore, the health risk of the technical/administrative job category might be underestimated. Finally, our results seem to suggest that workers with limitations might be "fragile", or more vulnerable, than expected in a broader sense of the term, both from nosological and temporal points of view. Further research with a higher level of evidence is needed to verify and confirm these findings.
The global burden of age-associated diseases continues to grow. In particular, the accelerating impact of neurodegenerative diseases on individuals, communities and societies necessitates more effective approaches to diagnosis, prognosis and treatment of such disorders. Hence, the establishment of imaging biomarkers for early detection of disease, progression monitoring, and therapeutic evaluation is of utmost importance. Yet, despite the scientific consensus on the benefits of scientific collaboration and consequently medical innovation including biomarker development, substantial barriers for sharing neuroimaging data remain, demanding a transformation in how scientific data are generated, made accessible, re-used and valued. These barriers range from technical and infrastructural limitations to legal and motivational challenges that hinder widespread adoption of open science practices. Here, we present a comprehensive overview of the current landscape of brain imaging data sharing in neurodegenerative disease research. We explore the status of preregistration, data harmonization and storage standardization, legal compliance, and researcher incentives. We highlight best practices before, during and after data generation and the pressing need for a coordinated strategy regarding simplified and unified legal frameworks compliant with the General Data Protection Regulation of the European Union. Finally, we advocate for the establishment of an academic credit system designed to reward data stewardship. Only with a combined effort from researchers, stakeholders and funding agencies including a sustained infrastructure investment and community education, the field can fully overcome inertia and move towards much-desired open science, thereby fully leveraging shared data to improve patient outcomes and scientific discovery.
The Oxford® Partial Knee (OPK; Zimmer Biomet, Warsaw, IN, USA) is a widely used unicompartmental knee arthroplasty (UKA) system. We report a case in which valgus malpositioning of the tibial component relative to the resection surface may have contributed to an early postoperative fracture. A 70-year-old woman underwent bilateral cementless OPK arthroplasty. On the left side, the tibial component was inserted in valgus alignment relative to a slight varus resection. Postoperative CT revealed a non-displaced tibial fracture. Internal fixation was performed, and bone healing proceeded uneventfully. The fracture was likely caused by valgus alignment of the component relative to the tibial cut, producing an eccentric loading, thereby generating a wedge effect and rotational force. Contributing factors for this malpositioned component placement may have included inadequate osteophyte removal, oversized component impingement on the medial collateral ligament (MCL), meniscal cuff interposition, and malaligned keel slot preparation. Bone union was achieved with stable fixation and biological bone ingrowth. Valgus malpositioning of the tibial component relative to the resection surface represents a previously unreported risk factor for periprosthetic tibial fracture in cementless OPK. Careful intraoperative technique can reduce this risk, and bone healing remains achievable following fracture.
Branched-chain keto acid dehydrogenase kinase (BCKDK) is a mitochondrial kinase that suppresses branched-chain amino acid (BCAA) oxidative catabolism by phosphorylating and inhibiting the branched-chain α-keto acid dehydrogenase complex. Beyond this canonical metabolic function, accumulating evidence indicates that aberrant BCKDK activation contributes to tumor metabolic rewiring, signaling adaptation, malignant progression and therapy resistance. This review summarizes the regulatory position of BCKDK in BCAA catabolism, its context-dependent functions across tumor types, and recent progress in BCKDK inhibitor development. Although selected non-oncological studies are discussed to inform inhibitor mechanism, pharmacology and safety, this review focuses on the oncology relevance of BCKDK. Particular attention is given to the transition from early proof-of-concept inhibitors to BT2-derived allosteric compounds, Pfizer-developed clinical candidates, and emerging non-BT2 scaffolds or alternative binding regions. A PubMed search was conducted to identify relevant studies on BCKDK, BCAA metabolism, cancer progression and BCKDK-targeted inhibitors. BCKDK is unlikely to function as a universal pan-cancer target. Its therapeutic value will depend on identifying tumor contexts with true BCKDK dependency, especially those relying on BCKDK-driven metabolic adaptation or downstream signaling. For BCKDK inhibitors, future development should integrate biochemical potency with mechanism-aligned conformational effects, long-term pharmacological consequences and biomarker-supported patient stratification.
Exercise is increasingly recommended for haemodialysis patients with chronic kidney disease, yet the evidence from meta-analyses remains fragmented, and its methodological quality has not been systematically evaluated. We systematically searched Embase, PubMed/MEDLINE, Cochrane Library, and Web of Science up to January 2026. We evaluated the methodological quality of studies using the 'Measurement Tool to Assess Systematic Reviews 2'. We used GRADE system to rate the evidence level for each outcome as high, moderate, low, or very low. We reviewed 11 meta-analyses. Aerobic exercise significantly improved dialysis adequacy (Kt/V) (weighted mean difference (WMD) = 0.08; 95% confidence interval (CI) = 0.00, 0.15), cardiorespiratory fitness (VO2 peak) (WMD = 2.07; 95% CI = 0.42-3.72), six-minute walk test (6MWT) (WMD = 64.98; 95% CI = 43.96-86.11); systolic blood pressure (SBP) (WMD = -10.07; 95% CI = -16.35, -3.78), C-reactive protein (CRP) (WMD = -3.28; 95% CI = -4.68, -1.88), and depression (standardised mean difference = -0.93; 95% CI = -1.32, -0.55). Aerobic exercise did not significantly affect diastolic blood pressure (DBP), physical component score (PCS), mental component score (MCS), or serum phosphorus. Resistance exercise significantly improved 6MWT (WMD = 68.50; 95% CI = 29.05, 107.96) and PCS (mean difference = 10.05; 95% CI = 2.95, 17.14) with no significant effects on Kt/V, CRP, or depression. Combined exercise improved VO2 peak, DBP, PCS, MCS, CRP, and depression, but not Kt/V, 6MWT, or SBP. Aerobic exercise may improve cardiorespiratory fitness, dialysis efficiency, inflammation, and depression; resistance may enhance muscle strength and physical function; combined training offers the broadest benefits. Individualized prescriptions are supported, but high-certainty evidence is lacking. PROSPERO: CRD420251244373.
In the face of increasing global demands and growing concerns regarding organizational sustainability, ethical leadership has emerged as a critical factor shaping employee wellbeing, commitment, and ethical behavior in the workplace. Accordingly, this study aimed to examine the influence of ethical leadership on workplace happiness, affective commitment, willingness to report ethical problems, ethical climate, and employee moral identity, while assessing the mediating roles of ethical climate and employee moral identity. This research is justified by the limited empirical evidence regarding the mechanisms through which ethical leadership influences employee attitudes and behaviors, particularly within integrated explanatory models that simultaneously consider both organizational and individual ethical factors. The study adopted an explanatory design, with 462 Peruvian workers. Participants were women (64.9%) and men (35.1%), aged between 21 and 64 years (M = 36.6; SD = 10.1). The model was statistically analyzed using PLS-SEM. The hypotheses of the proposed model were confirmed, demonstrating the influence of ethical leadership on workplace happiness, affective commitment, willingness to report ethical problems, ethical climate, and employee moral identity, highlighting in turn the mediating role of the ethical climate and employee moral identity in the proposed model. These findings suggest that ethical leadership functions as an integrative mechanism that links the organizational, psychological, and behavioral dimensions of employee performance. The study contributes to the literature by demonstrating the simultaneous mediating role of ethical climate and employee moral identity in explaining how ethical leadership influences model components. By providing evidence from the Peruvian healthcare sector, a context that is still underrepresented in organizational behavior research, this study expands the current theoretical understanding of ethical leadership. It offers perspectives for strengthening integrity, transparency, and sustainable people management practices in healthcare institutions.
Antibiotic resistance in wildlife is an emerging concern, as birds can serve as reservoirs and vectors for resistant bacteria. In this study, we investigated the diversity of bacteria belonging to the Enterobacterales order and their antibiotic resistance patterns in the unexplored Red-naped ibis (Pseudibis papillosa). It is a resident wading bird species in western India, i.e., Udaipur city, Rajasthan. It inhabits a wide range of environments, including urban areas, wetlands, agricultural fields, and fallow lands. Fecal samples (n = 45) were collected and a total of 60 bacterial isolates were analyzed for bacterial diversity and bacteria were characterized using biochemical, molecular, methods. Interestingly, four novel bacterial taxa from this host species were identified, i.e., Enterobacter mori, Enterobacter soli, Citrobacter freundii, and Leclercia adecarboxylata. Notably, E. mori and E. soli were reported for the first time in this bird species globally. Antibiotic susceptibility testing revealed high levels of multidrug resistance, with 40% of isolates resistant to at least three classes of antibiotics. Notably, resistance to clinically important antimicrobials, including the third-generation cephalosporin cefotaxime and reduced susceptibility to the carbapenem imipenem, was observed, raising concerns for spread of antibiotic resistance bacteria. Resistance to linezolid (100%) and rifampicin (100%) was also observed across isolates, consistent with the intrinsic resistance of Gram-negative bacteria to these agents. Our findings reported the presence of antibiotic-resistant bacteria in wild bird species which may contribute to the spread of antibiotic resistance through their fecal deposits and pose a serious risk to the health of humans and wild animals.
Objectives: Local positioning systems (LPSs) used in indoor team sports generate a large number of external load variables, often exceeding practical monitoring capacity. The redundancy and overlap among these variables make it difficult to identify the most informative metrics for performance analysis and load management. This study aimed to reduce the dimensionality of external load variables derived from LPS data and to identify data-driven external-load observation profiles using principal component analysis and clustering techniques. Methods: A total of 188 observations from indoor team sports (basketball, handball, and futsal) were analyzed. Continuous external load variables were standardized and subjected to principal component analysis (PCA), with component retention based on a ≥90% cumulative explained variance threshold. K-means clustering was applied in both the full standardized feature space and the PCA-reduced space. The optimal number of clusters was determined using silhouette analysis and the elbow method. Agreement between clustering solutions was assessed using Adjusted Rand Index (ARI) and Normalized Mutual Information (NMI). Cluster characteristics were further examined using descriptive statistics and variable separation analysis. Results: The first two principal components explained 53.7% of the total variance, representing high-intensity external load and neuromuscular load dimensions, while 12 components were required to exceed 90% cumulative explained variance. Clustering analysis consistently identified three moderately separated clusters in both the full and PCA-reduced spaces. The PCA-based solution demonstrated improved separation (silhouette = 0.362) compared to the full-space solution (silhouette = 0.319). Agreement between clustering approaches was high (ARI = 0.981; NMI = 0.971), indicating that dimensionality reduction largely preserved the main clustering structure within the analyzed dataset. The most discriminative variables included jump load, acceleration load, metabolic power, and anaerobic activity distance. Conclusions: A large set of external load variables can be reduced into interpretable latent dimensions that support exploratory external-load profile identification. The combination of PCA and clustering provides an exploratory and structure-preserving framework for summarizing complex external-load datasets and identifying latent load dimensions. These findings may assist future monitoring strategies; however, the practical utility of the identified profiles requires prospective validation before implementation in training-load management.
The regular intake of moderate doses of coffee is increasingly recognized as a lifestyle factor associated with a lower incidence of depressive-like conditions; however, there is still a debate on the relative effects of caffeinated and decaffeinated coffee. We now resorted to a model of chronic unpredictable stress to compare how the regular drinking of caffeinated and decaffeinated coffee impacted on stress-induced deterioration of mood and memory in adult mice. Stressed mice displayed lower weight gain, increased locomotion and greater anxiety, lower motivation in the splash test, less struggling and greater immobility in the forced swimming test, increased anhedonia in the sucrose preference test and decreased spatial reference memory in the object displacement and modified Y-maze tests. The continuous intake of caffeinated, but not decaffeinated, coffee attenuated all these stress-induced mood and memory deficits. Moreover, the intake of caffeinated, but not decaffeinated coffee, also attenuated the stress-induced decrease of long-term potentiation in hippocampal synapses and of brain-derived neurotrophic factor levels in frontocortical synapses, a neurophysiological and neurochemical signature of mood deterioration. These results prompt caffeine as a prominent coffee constituent responsible for the benefits of the regular intake of coffee on stress-induced behavioral deficits.
Although therapeutic options for hidradenitis suppurativa (HS) continue to expand, unmet needs remain substantial. We evaluated the efficacy and safety of povorcitinib (an oral, highly selective Janus kinase 1 (JAK1) inhibitor) in patients with moderate to severe HS in two randomized trials. STOP-HS1 and STOP-HS2 were identically designed, randomized, double-blind, placebo-controlled phase 3 trials. Adults with moderate to severe HS were randomized 2:2:1:1 to once-daily treatment through week 54: povorcitinib 45 mg; povorcitinib 75 mg; placebo with crossover at week 12 to povorcitinib 45 mg; or placebo with crossover at week 12 to povorcitinib 75 mg. The primary endpoint was HiSCR50 (≥50% decrease in total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining tunnel count) at week 12. STOP-HS1/STOP-HS2 enrolled 608/619 patients, respectively. In both studies, both povorcitinib doses met the primary endpoint; in STOP-HS1, 82/204 (40%) patients in the povorcitinib 45-mg group and 82/202 (41%) in the 75-mg group versus 60/202 (30%) in the placebo group achieved HiSCR50 (OR (95% CI) 45 mg: 1.6 (1.1-2.5), P = 0.0240; 75 mg: 1.6 (1.1-2.4), P = 0.0214); corresponding values for STOP-HS2 were 88/208 (42%) and 88/208 (42%) versus 58/203 (29%; OR (95% CI) 45 mg: 1.8 (1.2-2.8), P = 0.0035; 75 mg: 1.9 (1.2-2.8); P = 0.0033). Through week 12, across STOP-HS1/STOP-HS2, serious treatment-emergent adverse events (AEs) occurred in 1-2% of patients across povorcitinib doses and in 2-3% with placebo; through week 54, serious AEs occurred in 5%/6% of patients receiving 45-mg/75-mg povorcitinib, respectively. The most frequent AEs among patients treated with 45-mg/75-mg povorcitinib were acne (17%/20%), nasopharyngitis (10%/12%) and upper respiratory tract infection (11%/10%). One death of undetermined etiology was reported and deemed unrelated to treatment. No new or unexpected safety findings were identified. Oral povorcitinib demonstrated significant improvements in HiSCR50 versus placebo and a favorable safety profile in patients with moderate to severe HS. ClinicalTrials.gov registration: NCT05620823 and NCT05620836 .
Glucocorticoid resistance syndrome (GRS) is a rare hereditary disorder caused by pathogenic variants in NR3C1, characterized by marked phenotypic heterogeneity and frequent misdiagnosis as primary aldosteronism or subclinical Cushing's syndrome. We report a family harboring a novel NR3C1 frameshift variant and provide an integrated characterization of its clinical and biochemical features. By combining structural prediction, tissue- and single-cell-level expression analyses, in silico virtual gene perturbation, and systematic literature review, we evaluated the potential functional impact and clinical relevance of this variant. Comprehensive clinical phenotyping, steroid metabolomic profiling, adrenal CT imaging, and segregation analysis were performed in the proband and his father. AlphaFold3 was used to predict the structures of wild-type and mutant GRα proteins. Variant pathogenicity was assessed following ACMG/AMP criteria. Cross-tissue and single-cell expression patterns of NR3C1 were analyzed, and in silico virtual knockout analysis was performed to generate exploratory hypotheses regarding potentially affected biological pathways. A systematic review was conducted to summarize previously reported GRS cases, their variants, and associated phenotypes. Two affected males across successive generations presented with refractory hypertension without Cushingoid features. Steroid profiling demonstrated mild hypercortisolemia with elevated ACTH, marked increases in 11-deoxycorticosterone and 11-deoxycortisol, suppressed renin, and low-to-normal aldosterone, consistent with ACTH-driven accumulation of mineralocorticoid precursors. Sequencing identified a novel NR3C1 frameshift variant, c.923dupG (p.Ala309Serfs*6), absent from population databases and co-segregating with the familial phenotype. Structural prediction indicated premature termination within the N-terminal transactivation domain, supporting loss of the downstream DNA-binding and ligand-binding domains. According to ACMG/AMP criteria, the variant was classified as pathogenic. In silico virtual perturbation analysis suggested that NR3C1 dysfunction may extend beyond a linear defect in glucocorticoid signaling, potentially influencing neuroendocrine communication, extracellular matrix regulation, protein translation, and developmental pathways. Literature review identified 66 reported GRS cases encompassing substantial phenotypic variability, with cardiovascular events documented in some carriers of N-terminal or truncating variants. We describe a novel exon 2 NR3C1 frameshift variant that co-segregates with a characteristic GRS hormonal profile and is supported by clinical, genetic, and structural evidence. This case expands the genotype-phenotype spectrum of NR3C1-related GRS. The potential relationship between N-terminal truncating variants and cardiovascular complications remains hypothesis-generating and requires validation in larger cohorts and functional studies. Our findings underscore the importance of considering NR3C1-related GRS in patients presenting with resistant hypertension accompanied by a distinctive steroid profile.
Vogt-Koyanagi-Harada syndrome (VKHS) has been established as an autoimmune disease targeting melanocytes; however, its underlying mechanism remains obscure. We previously found an increased proportion of CD14+CD56+ monocyte (CD56+ monocyte thereafter) accompanied by decreased T cell frequency in the peripheral blood of patients with VKHS treated with glucocorticoids (GCs), suggesting the immunoregulatory function of this monocyte. However, whether CD56+ monocyte is a bona fide regulatory monocyte subset in VKHS is to be determined. Through morphological, transcriptomic, and immunophenotypic analyses, we confirm that CD56+ monocyte constitutes a distinct immunoregulatory monocyte subset compared with CD56- monocyte and NK cell. Upon lipopolysaccharide (LPS) stimulation, CD56+ monocytes showed greater capacity to secrete pro-inflammatory cytokines (TNF-α, IL-23, IL-8, and IL-6) and anti-inflammatory cytokine IL-10 compared with CD56- monocytes and NK cells. Interestingly, secretion of granzyme B and perforin is observed in CD56+ monocytes but not CD56- monocytes in steady-state conditions, albeit at lower levels than NK cells. Moreover, CD56+ monocytes demonstrate superior phagocytosis, antigen processing, and migration abilities but intermediate adhesion capabilities compared with CD56- monocytes and NK cells. Importantly, monocytes treated in vitro and derived from GC-treated patients with VKHS harbor an increased proportion of CD56+ monocytes, and exhibit enhanced migration and reduced adhesion, along with stronger capacity to inhibit CD4+ T cell proliferation. These findings highlight the importance of CD56+ monocytes, as an independent regulatory monocyte subset, in response to GC therapy in the context of acute VKHS. The potential mechanism revealed in this study will provide insight into novel treatment strategies of VKHS by harnessing CD56+ monocytes.
The in vivo performance of tissue-engineered heart valves remains constrained by a persistent early failure triad at the blood-material interface, namely thrombosis, unresolved inflammation, and slow endothelialization. Here, a bioinstructive multilayer valve scaffold is engineered to address these interfacial barriers through spatially integrated structural and biological functions. The scaffold comprises a digitally programmable 3D-printed framework, a silk fibroin wrapping layer, and a hydrogel biointerface incorporating Arg-Gly-Asp/GelMA adhesive cues together with H2S-releasing microgels. This layered design endows the construct with valve-relevant tensile properties while simultaneously programming the immune-endothelial microenvironment. The hydrogel biointerface promotes endothelial migration, proliferation, and angiogenic activity, whereas sustained H2S delivery biases macrophages toward a pro-resolving M2-like phenotype and suppresses inflammatory activation. Transcriptomic analysis further reveals coordinated upregulation of endothelial programs related to endothelial repair, migration, and proliferation, accompanied by attenuation of stress- and inflammation-associated responses. In vivo, the scaffold mitigates thromboinflammatory reactions, shows preliminary anti-calcification performance, and supports endothelialization under blood-contacting conditions. Together, this work establishes a layered bioactive engineering approach that converts a passive 3D-printed structural scaffold into a regenerative, hemocompatible, and immunoregulatory biofunctional valve scaffold. This strategy offers a promising design principle for the further development of regenerative valve scaffolds.