Search Results (6,688)

Background/Aim: Albuminuria is a clinical marker associated with microvascular involvement and an independent predictor of cardiovascular risk. Polycystic ovary syndrome (PCOS) is associated with early metabolic and vascular abnormalities; however, whether albumin excretion differs across PCOS phenotypes remains unclear. This study aimed to evaluate the urinary albumin-to-creatinine ratio (U-ACR) across PCOS phenotypes and to examine its association with metabolic parameters. Materials and Methods: In this cross-sectional study, 180 women aged 18–35 years with PCOS and 51 age-matched healthy controls were included. PCOS phenotypes were classified according to the Rotterdam criteria as Phenotype A (n = 96), Phenotype B (n = 19), Phenotype C (n = 35), and Phenotype D (n = 30). Insulin resistance was assessed using the homeostasis model assessment for insulin resistance (HOMA-IR). Urinary albumin and creatinine levels were measured in morning urine samples, and U-ACR was calculated. Results: Age was comparable across all groups. Body mass index, waist circumference, diastolic blood pressure, and HOMA-IR were significantly higher in Phenotype A compared with controls and other phenotypes, reflecting a more adverse metabolic profile. Serum creatinine levels were similar across all groups. Despite this metabolic profile in Phenotype A, U-ACR was significantly elevated only in Phenotype B compared with controls (p = 0.018), and Phenotype D (p = 0.016). No significant correlations were observed between U-ACR and age, body mass index, or HOMA-IR. When participants were categorized according to U-ACR levels (<30, 30–299.9, and ≥300 mg/g creatinine), no significant differences in category distribution were observed between the total PCOS cohort, phenotype subgroups, and controls. Conclusion: Among PCOS phenotypes, U-ACR elevation was observed exclusively in Phenotype B despite similar renal function markers. This finding, in the presence of a more adverse metabolic profile in Phenotype A, suggests a dissociation between metabolic burden and early microvascular involvement across PCOS phenotypes. These findings suggest a potential phenotype-specific pattern that warrants further investigation. Full article

Yellow rust (Puccinia striiformis f. sp. tritici) is one of the most destructive diseases in wheat (Triticum aestivum L.) in Kazakhstan, causing significant yield losses. Owing to the high susceptibility of widely cultivated varieties, the development of resistant genotypes remains a key objective for sustainable crop protection. The aim of this study was to evaluate the resistance of wheat lines to yellow rust and to identify effective resistance genes. The research was conducted under artificial infection conditions using hybrid populations of the F2–F5 generations. The genotypes were assessed and ranked according to their resistance levels, and molecular markers were applied to detect resistance genes. Significant variability in disease response was observed. Analysis of variance revealed a strong effect of genotype on the infection coefficient (p < 0.001). Lines from later generations (F5) presented lower infection levels. Most genotypes carried the Yr5 gene, highlighting its major role in resistance, whereas Yr10 was less common. Yr15 and Yr18 were detected in some lines and were associated with partial (adult plant) resistance. Moderately susceptible forms predominated, indicating widespread quantitative resistance. However, highly resistant lines (CI = 0–1) and immune forms were identified, representing valuable material for breeding programs. Full article

Mass spectrometry and high-throughput sequencing have been introduced into clinical bacteriology. We characterized strain IMB-1, previously isolated from the cerebrospinal fluid of a child, as Pseudoxanthomonas kaohsiungensis and analyzed its biological properties, resistance phenotype, and complete genome. The IMB-1 strain displayed amylolytic, weak lipolytic activities, and it exhibited a phenotypic resistance profile only for aminoglycosides. The dDDH calculation based on the complete genome sequence showed that strain IMB-1 was closely grouped with the type strain P. kaohsiungensis DSM 17583, and the dDDH (d4) value was 70.1%. A comparative pan-genome analysis was performed for four P. kaohsiungensis genomes, revealing a substantial shared core genome. The IMB-1 genome contained 508 unique gene clusters, representing the largest strain-specific gene set among the analyzed genomes, suggesting genomic plasticity and adaptation to the host-associated environment. Genome annotation revealed genes responsible for antibiotic, disinfecting agent, and antiseptic resistance. Gene clusters exhibiting the potential to form biofilms, adhere to the epithelial surface, and exhibit resistance to stress factors were identified. Our study demonstrates that strain IMB-1 is a potential opportunistic pathogen with significant pathogenic potential. The application of high-resolution whole-genome sequencing data in public health for pathogen identification and monitoring can improve the accuracy of infection source determination, reduce the scale and burden of outbreaks, and identify and quantify antimicrobial resistance in pathogens. Full article

Background/Objectives: Adult epilepsy is clinically heterogeneous, and individual clinical predictors may not fully capture the multidimensional burden associated with drug-resistant epilepsy (DRE). This study aimed to identify latent clinical phenotypes in adults with epilepsy and examine their cross-sectional associations with DRE and broader disease burden. Methods: This regional observational cohort study used a source database of 1100 patients with epilepsy. After excluding two patients aged <18 years, the adult analytic cohort included 1098 patients. Complete-case latent class analysis (LCA) was performed in 1054 patients using age at onset, disease duration, seizure type, seizure frequency, serial seizures/status, postictal confusion, neurological status, neuroimaging category, and number of antiseizure medications. Model selection was based on statistical fit, class size, and clinical interpretability. Internal clinical validation outcomes included DRE, quality of life, cognitive screening, and stigma scores. Post hoc characterization described the classes by epilepsy etiology, derived epilepsy type, and seizure categories aligned with current terminology. Results: A three-class solution was selected, with class sizes of 314, 465, and 275. DRE prevalence increased stepwise across classes: 5.7%, 14.2%, and 33.1%, respectively (p < 0.001). In adjusted analysis, Class 2 had higher odds of DRE than Class 1 (odds ratio 2.70, 95% confidence interval 1.56–4.67), while Class 3 showed the strongest association (odds ratio 8.19, 95% confidence interval 4.15–16.16; both p < 0.001). Higher-burden classes showed lower quality-of-life and cognitive scores and higher stigma scores. Conclusions: LCA identified three clinically interpretable, burden-enriched phenotypic profiles associated with a stepwise gradient in DRE and broader multidimensional disease burden. These cross-sectional profiles may provide a useful framework for describing clinical heterogeneity in adult epilepsy and generating hypotheses for future validation studies. Full article

Candidozyma auris (formerly known as Candida auris) has emerged as a formidable clinical fungal pathogen as a result of its multidrug resistance and persistent colonization capabilities. In this study, three clinical C. auris strains (namely C. auris strain 01, C. auris strain 03, and C. auris strain 13) with distinct origins were characterized to investigate their phenotypic variations and mechanisms of azole resistance. Comprehensive profiling revealed significant inter-strain differences in biofilm formation, cell surface hydrophobicity, adhesion capacity, and phospholipase activity. Testing for antifungal susceptibility showed that the three clinical strains exhibited different minimum inhibitory concentrations for multiple azoles (fluconazole, voriconazole, and itraconazole) and echinocandins (anidulafungin and micafungin). Sequencing identified Y132F mutations in the ERG11 gene of the three clinical strains. Mechanistic investigations demonstrated that fluconazole exposure significantly upregulated the expression of efflux pump genes (CDR1 and CDR2) and the genes encoding their transcriptional regulators (MDR1 and TAC1b). In a murine skin colonization model, comparing data from the standard strain C. auris strain CBS12766 and clinical strains of C. auris strain 03 and C. auris strain 13 exhibited a significantly higher fungal burden of tissue, whereas strain C. auris strain 01 showed an intermediate level. Host immunity response analysis revealed that expression of the IL-1β gene was significantly elevated in C. auris strain CBS12766-infected mice, while expression of IL-6 and CXCL-1 genes was predominantly increased in the C. auris strain 01, with TNF-α gene expression levels being comparable across all strains. Histopathological examination confirmed local infiltration of inflammatory cells and mild epidermal edema, indicating active host immune engagement. Overall, our findings highlighted substantial phenotypic heterogeneity, different colonization capacities, and differences in expression of inflammatory cytokines among the C. auris strains. Further investigations into fluconazole-response mechanisms identified enhanced efflux pump activity, along with ERG11 gene Y132F mutations and transcription factor modulation among these clinical strains. Full article

Dermatophytosis remains one of the most prevalent superficial fungal infections worldwide and is increasingly encountered as a persistent or difficult-to-treat syndrome. A major clinical problem is that apparent treatment failure is often attributed to antifungal resistance, although many cases are instead driven by diagnostic uncertainty, corticosteroid-modified disease, reinfection, inadequate exposure, poor adherence, and limited drug delivery within keratinized tissues. This narrative review was developed to clarify the distinction between true antifungal resistance and clinical recalcitrance, with particular attention to terbinafine-resistant Trichophyton species, Trichophyton indotineae, tinea incognito, onychomycosis, dermatophytoma, and high-barrier skin and nail infections. We synthesized peer-reviewed literature and guideline-level evidence addressing epidemiology, molecular mechanisms of resistance, clinical phenotypes of recalcitrance, diagnostic escalation, therapeutic decision-making, and antifungal delivery in keratinized tissues. The review contributes a dermatology-centered conceptual framework in which persistent dermatophytosis is interpreted through both microbiological resistance and modifiable recalcitrance drivers. This approach emphasizes confirmation of fungal disease when indicated, phenotypic and anatomic classification, avoidance of inappropriate corticosteroid combinations, optimization of dose, duration, vehicle, and adherence, measures to improve drug access and reduce protected fungal burden in high-barrier disease, and prevention of reinfection from reservoirs. The proposed framework may support more rational antifungal use and reduce unnecessary escalation; however, it is based on narrative synthesis rather than a systematic review or prospective validation. Additional studies are needed to determine how such structured clinical approaches affect clinical outcomes, relapse rates, antifungal exposure, and resistance emergence in real-world dermatology practice. Full article

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with poor survival rates of late-stage disease. While immune checkpoint blockade (ICB) therapy has transformed treatment for mismatch repair-deficient (MMRd)/microsatellite instability-high (MSI-H) tumors, most CRC cases are mismatch repair-proficient (MMRp)/microsatellite-stable (MSS) and derive little to no benefit from current immunotherapy regimens. Tumor-associated macrophages (TAMs) constitute a significant component of the tumor microenvironment (TME) and exhibit a phenotypic gradient between pro-inflammatory (M1-like) and anti-inflammatory, immunosuppressive (M2-like) states. Although their polarization status is increasingly recognized as a key modulator of immunotherapy efficacy in CRC, a comprehensive synthesis of the literature regarding macrophage polarization and its relevance to improving CRC immunotherapy remains lacking. Methods: A systematic literature search was conducted across PubMed, EMBASE, and ScienceDirect from inception to December 2025 using terms encompassing macrophages, immunotherapy, immune checkpoint expression, colorectal cancer, and microsatellite stability status. Title, abstract, and full-text screening were performed independently by multiple authors. Sixty-five studies were included following PRISMA guidelines. The protocol was prospectively registered on PROSPERO (ID: CRD420251244320). Results: Three key themes were identified: (1) macrophage-mediated mechanisms of resistance to ICB, including M2 polarization driven by the PI3Kγ, STAT3, mTOR, and SIRT-1 axes, immunosuppressive cytokine production (IL-10, TGF-β), and altered immune checkpoint ligand expression; (2) macrophage polarization status and associated biomarkers as prognostic indicators of therapeutic response; (3) emerging macrophage-targeted therapeutic strategies in ongoing clinical trials, including CSF1R inhibitors, CD40 agonists, CD47/SIRPα blockade, and STING agonists. Conclusions: TAM polarization is a critical determinant of immunotherapy resistance and patient prognosis in CRC. Macrophage-targeted strategies, particularly M2-to-M1 repolarization approaches used in combination with existing ICB regimens, represent a promising avenue for expanding immunotherapy efficacy beyond MSI-H disease. Further translational research and randomized controlled trials are needed to validate these targets clinically. Full article

Asthma is defined as a chronic airway inflammatory disorder with over-activation of the immune system accompanied by the inability to resolve inflammation. SPMs are novel potent lipid mediators that play an important role in maintaining inflammation homeostasis and macrophages’ functional plasticity. This review will look into the potential function of SPM-programmed macrophage reprogramming as a novel therapeutic strategy for asthma. Unlike current anti-inflammatory treatments, which only focus on suppressing inflammation, SPMs can actively drive the inflammation resolution phase by promoting efferocytosis and wound healing while maintaining the defense against infection. In experimental asthma animal models, lipoxins, resolvins, protectins, and maresins have been demonstrated to alleviate inflammation and airway hyperresponsiveness, shift macrophages towards pro-resolving phenotypes and thus facilitate the resolution process. Levels of some SPM subclasses were found to be reduced in severe or uncontrolled asthmatics, indicating defective resolution pathways may contribute to asthma persistence. The mechanisms include down-regulation of pro-inflammatory cytokines, alteration of macrophage phenotype, improvement of immune homeostasis in the airway milieu, etc. These molecules have become highly promising therapeutic agents after the development of metabolically stable analogs, receptor-targeted agonists, and an improved delivery system. Multi-omics studies coupled with patient stratification based on biomarkers will potentially help in the future to develop personalized resolution-based therapy, in particular for those steroid-resistant and non-type 2 asthmatics. Nevertheless, the evidence provided so far is mainly preclinical; more challenges in terms of pharmacokinetics, formulation and formulation development, regulatory agency approval, and clinical validation remain and will be overcome through further studies, thus warranting investigation into SPM-mediated strategies for asthma and other chronic inflammatory diseases. Full article

Sjögren’s disease (SjD) remains one of the few major systemic autoimmune diseases without an approved disease-modifying therapy, despite decades of pathogenic insight and several randomised trials. We contend that these repeated failures reflect not intrinsic therapeutic refractoriness, but trial designs insufficiently aligned with the underlying biological heterogeneity of SjD. We propose a tripartite framework in which SjD is organised around three dominant biological axes: an interferon-driven systemic axis, a B-cell/lymphoproliferative axis, and a symptom/fibro-structural axis. Each axis carries its own characteristic biomarkers, histopathology, prognostic features, candidate endpoints, and therapeutic targets, and each implies a distinct trial enrolment strategy. Recent positive trials—phase III for ianalumab in NEPTUNUS-1/2, phase 2b for iscalimab in TWINSS, phase 2 for nipocalimab in DAHLIAS, and phase 2 for dazodalibep in a phenotype-defined symptom-dominant cohort—illustrate that meaningful clinical benefit becomes detectable once stratification is aligned to biology. By integrating molecular endotypes, validated biomarkers, composite endpoints, and phenotype-matched therapies onto a single explicit architecture, SjD shifts from a recurring example of translational failure to a model for precision medicine in heterogeneous autoimmune disease. The central message is that SjD may be less intrinsically treatment-resistant than it has historically been treatment-mistargeted. Full article

Introduction: Several Enterobacterales species harboring New Delhi metallo-β-lactamase (NDM-1) have been reported worldwide. Among them is Providencia stuartii (P. stuartii), an emerging pathogen in nosocomial infections. Objective: This study aimed to perform the clinical and genomic characterization of NDM-1-producing P. stuartii isolates recovered from hospitalized patients during the COVID-19 pandemic in Southern Brazil. Materials and Methods: A retrospective observational study was conducted between April and September 2021 at a Brazilian teaching hospital. Fifty P. stuartii isolates were identified, and carbapenem-resistant isolates underwent phenotypic and molecular characterization. Genetic relatedness was assessed by Enterobacterial Repetitive Intergenic Consensus PCR (ERIC-PCR), and selected isolates were subjected to whole-genome sequencing using the Illumina NextSeq platform to determine sequence types, resistance genes, virulence determinants, and plasmid content. Statistical analyses were performed using SPSS version 20.0. Results: Among the 50 isolates, 21 (42%) harbored the blaNDM-1 gene. Most isolates were recovered from tracheal aspirates (57.2%), followed by blood (23.8%), urine (9.5%), and skin and soft tissue samples (9.5%). Significant associations were observed between NDM-1-producing isolates and SARS-CoV-2 infection (p = 0.013), central venous catheter use (p = 0.012), mechanical ventilation (p = 0.006), hemodialysis (p = 0.033), previous antimicrobial exposure, and mortality (p = 0.021). Genomic analysis revealed the presence of blaNDM-1, blaOXA-1, and multiple resistance determinants associated with aminoglycosides, fluoroquinolones, macrolides, tetracyclines, and folate pathway inhibitors. ERIC-PCR demonstrated low genetic variability among isolates, suggesting possible clonal dissemination within the hospital environment. Conclusions: This study reports the emergence of NDM-1-producing P. stuartii during the COVID-19 pandemic in a Brazilian teaching hospital. The low genetic variability among isolates and the multidrug-resistant profile highlight the potential for nosocomial dissemination and reinforce the importance of genomic surveillance and infection control strategies. Full article

Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly prevalent and now recognized as a systemic syndrome with diverse clinical phenotypes and multiorgan involvement. The predominant clinical phenotype has evolved from patients with isolated hypertensive heart disease to individuals with cardiometabolic (CM) abnormalities [obesity, insulin resistance, increased waist circumference (a surrogate for visceral adiposity), dyslipidemia, type 2 diabetes, and hypertension] that result in metabolic alterations leading to CM-HFpEF. Indeed, CM-HFpEF and metabolic dysfunction-associated fatty liver disease are recognized as two sides of the same coin. Chronic systemic inflammation is a defining pathophysiologic feature of CM-HFpEF, with visceral adipose tissue serving as a central driver. In this regard, lifestyle changes, including diet and exercise, are crucial for managing HFpEF. Several recent studies have shown that exercise training (aerobic and resistance combined) with or without calorie restriction is an effective therapeutic management strategy for improving exercise capacity, physical function, and quality of life in patients with clinically stable HFpEF. Also, the pharmacologic interventions that have proven beneficial in HFpEF so far (sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists) are effective due to their metabolic protective effects. In this review, we outline the current available evidence on lifestyle interventions in HFpEF management and therapeutics, discussing their modalities and potential mechanisms. Full article

Banana Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4), poses a severe threat to global banana production, and breeding resistant cultivars remains the most effective control strategy. Mutation breeding, including radiation mutagenesis and somaclonal variation, has become a primary approach for developing resistant germplasm in triploid Cavendish bananas. However, whether secondary bud-sport selection from resistant somaclonal lines inadvertently compromises original resistance mechanisms at the molecular level remains poorly understood. In this study, we generated 44 mutants from Baxi jiao via ⁶⁰Co γ-irradiation and selected five lines with distinct phenotypic variations. We also collected somaclonal variant lines GCTCV-218, GCTCV-119, GCTCV-105, their bud-sport derivatives (NK_No.1, NTH, RK_No.1), and the radiation-induced resistant mutant ‘Zhongre No.1’. Using whole-genome resequencing and transcriptome analysis, we systematically compared the genetic and transcriptomic outcomes of these breeding strategies. Radiation mutagenesis induced substantial genomic structural variations and generated novel expression patterns of defense-related genes. In contrast, while bud-sport derivatives of GCTCV-218 remained genetically similar to their parent, they exhibited significant downregulation or loss of key resistance gene expression, particularly PR-1 family members. Our findings reveal that phenotype-driven somaclonal selection can inadvertently erode original resistance mechanisms, and we recommend prioritizing radiation mutagenesis for developing banana cultivars with stable and durable resistance to Foc TR4. Full article

Background: Immune mechanisms are increasingly implicated in the heterogeneity of schizophrenia spectrum disorders. Cytomegalovirus (CMV), a latent immunomodulatory herpesvirus, is linked to cognitive and immunological alterations, but its electrophysiological correlates remain largely unexplored. This study investigates the relationships among CMV serostatus, EEG features, inflammatory markers, and clinical–cognitive variables. Methods: In this prospective cross-sectional study, 123 patients with schizophrenia spectrum disorders underwent integrated clinical, cognitive, laboratory, and qualitative visual EEG assessments. CMV exposure was determined via IgG serology. Results: Global electroencephalographic EEG organization did not differ by CMV serostatus. However, a descriptive increase in resting-state sharp-wave discharges was observed in CMV-seronegative patients, independent of baseline cortical rhythms. Immunologically, CMV-seropositive individuals exhibited significantly higher total leukocyte counts, consistent with latent viral immune remodeling rather than overt systemic inflammation. Clinically, CMV-seropositive patients demonstrated descriptively higher scores on the disorganization dimension derived from the PANSS (Positive and Negative Syndrome Scale) five-factor consensus model. While these variations did not retain statistical significance after multiple testing correction, separate dimensional analyses revealed that patients exhibiting sharp waves demonstrated better overall cognitive functioning and superior performance within a memory-related item grouping. Notably, the presence of sharp-wave activity was independent of both peripheral inflammatory profiles and treatment-resistant status, underscoring a distinct electrophysiological phenotype. Conclusions: CMV exposure represents a modulating biological background associated with corrected leukocyte elevations and subtle electrophysiological variability, rather than a direct determinant of global clinical severity. The nominal EEG variations and their independent link to better-preserved memory performance highlight non-linear neuroimmune interactions. Given the cross-sectional design, these exploratory patterns warrant a non-causal interpretation but outline a foundation for future longitudinal investigations. Full article

The oncocytic variant of adrenocortical carcinoma (OACC) represents an exceptional type of adrenal malignancy, with heterogenous presentation. Currently, the genetic and molecular spectrum remains an open matter. A 20-year-old adult was accidentally found with a 7.2 cm adrenal tumor and underwent an open right adrenalectomy with OACC confirmation. Post-adrenalectomy positron emission tomography/computed tomography was negative. Immunohistochemistry was positive for calretin, inhibin, steroidogenic factor 1; Ki67 of 20%. Microsatellite instability was 7.61. Lin–Weiss–Bisceglia score showed 2 major criteria [mitoses 6/50 HPF + positive atypical mitoses], the reticuline algorithm (disrupted reticuline network + mitoses 6/50 HPF) was consistent for a malignant behavior, the Helsinki score was of 48. Next generation sequencing identified a likely pathogenic variant of CEL gene (heterozygote, c.539-2A>G) in peripheral blood and two pathogenic variants in the tumor: exon 48, NF1 gene [c.7159_7164del p.(N2387_F2388del)] and exon 6, TP53 gene [c.596delG p.(G199Efs*48)]. Polycystic ovary syndrome type A has been diagnosed as teenager with no phenotype change before the tumor detection. After surgery, oocyte retrieval and cryopreservation upon ovarian stimulation protocol (OSP) was performed before starting mitotane therapy. To the best of our knowledge, this is a novel genetic configuration in OACC with an impact on prognosis to be determined. Hyperandrogenemia stands on a dual source (potential CEL-driven insulin resistance for the ovary and OACC-originating for the adrenal glands). Also, this is the first case to receive OSP in OACC, noting that a tailored multidisciplinary management is mandatory. Full article

Defective seed filling, which manifests as seed wrinkling, severely impairs the yield and commercial quality of soybean crops. Soybean varieties independently developed in Heilongjiang Province exhibit distinct phenotypic variations in seed wrinkling across diverse ecological planting regions, whereas the molecular and physiological mechanisms driving such differences remain largely uncharacterized. In this study, two soybean genotypes with divergent heat resistance, namely, the heat-sensitive cultivar HH43 and the heat-tolerant cultivar HN76, were planted in three distinct ecological sites for comparative analysis. Statistical results indicated that ecological conditions serve as the predominant factor regulating seed-wrinkling variation, with high temperatures occurring during the seed-filling stage identified as the key abiotic stress trigger. Excessively high ambient temperatures triggered abnormal sucrose accumulation in the pod husks of heat-vulnerable HH43, disrupting the coupling relationship between sucrose metabolism and energy supply and thereby restricting starch biosynthesis in developing seeds. Transcriptome profiling combined with weighted gene co-expression network analysis (WGCNA) further demonstrated that heat stress significantly suppressed the expression of energy transport-related genes and induced the dysregulated expression of starch synthesis-associated genes in susceptible soybean plants, and these transcriptional alterations were further verified via qRT-PCR assays. Collectively, short-term extreme high temperatures interrupt the carbon transport and allocation process from pod husks to seeds in heat-sensitive soybean cultivars. By contrast, heat-tolerant genotypes can sustain a stable physiological metabolism and molecular regulatory networks to effectively cope with high-temperature stress during the seed-filling period. Full article