Search Results (1,236)

Background/Objectives: Interstitial pneumonia with autoimmune features (IPAF) is a recently defined entity characterized by interstitial lung disease (ILD) with clinical, serological, and radiological features suggestive of autoimmunity that do not fulfil the criteria for a defined connective tissue disease (CTD). This study aimed to evaluate the clinical characteristics, treatment modalities, and outcomes of patients with IPAF in a tertiary referral center. Methods: We retrospectively analyzed 72 patients who fulfilled the IPAF classification criteria. Demographic, clinical, serological, radiological, pulmonary function, treatment, and survival data were collected and evaluated. Logistic regression analysis was performed to identify factors associated with mortality. Results: The cohort consisted of 62.5% female patients, with a mean age of 62.7 (SD, 10.4) years at diagnosis. The most frequent radiological pattern was nonspecific interstitial pneumonia (83.3%). Raynaud’s phenomenon (6.9%) and arthritis (2.8%) were the most common rheumatological manifestations. Antinuclear antibodies positivity at titers ≥1:320 was observed in 27.8% of patients. Azathioprine was the most frequently prescribed agent (20.8%), followed by mycophenolate mofetil (11.1%). After a median follow-up of 30.1 months (IQR, 52.8), 16 patients (22.22%) died, with a 5-year survival rate of 70%. Glucocorticoid therapy at doses ≥20 mg/day was independently associated with increased mortality (OR 6.13 (95% CI 1.17–32.21). Conclusions: IPAF predominantly affects middle-aged females. Glucocorticoid use at doses ≥20 mg/day was associated with mortality; however, this observational association may reflect underlying disease severity rather than a causal effect of high-dose treatment. Further prospective studies are needed to optimize management strategies in patients with IPAF. Full article

Liver fibrosis, the progressive accumulation of scar tissue resulting from chronic liver disease, is increasingly recognized as a multi-system condition, the effects of which extend beyond the liver, affecting brain health. Dementia, characterized by progressively impaired cognition sufficient to impede daily functioning, is a major global health issue with incompletely defined risk factors and pathogenic precursors. To examine the relationship between liver fibrosis and cognitive outcomes, we conducted a comprehensive PubMed literature search, and human studies published in English were included. Evidence is synthesized on the pathophysiology and clinical significance of liver fibrosis, types of dementia, and studies supporting the association between liver fibrosis and cognitive impairment. Meta-analytic data indicate that liver fibrosis is associated with an approximately 30% increased risk of incident dementia (pooled hazard ratio ~1.3), with progressively higher risks across more advanced fibrosis stages. Putative pathomechanisms, potentially modulated by age and sex, include chronic systemic and neuro-inflammation, insulin resistance, vascular dysfunction, and a perturbed intestinal microbiota–liver–brain axis. Non-invasive liver fibrosis diagnostics, advanced neuroimaging, and biomarkers represent key tools for assessing risk. In conclusion, liver fibrosis is a systemic condition that can affect brain health. Early detection, thorough risk assessment and interventions, such as lifestyle changes, metabolic therapies, and antifibrotic treatments, may help protect neural function. Key research gaps are identified, with suggestions for improving understanding of liver fibrosis’s connection to dementia or cognitive impairment. Full article

Autoantibodies have long been regarded as passive reflections of immune dysregulation in connective tissue diseases (CTDs). Recent advances in systems immunology and molecular pathology have fundamentally redefined them as active molecular fingerprints that delineate distinct disease endophenotypes with predictive power for clinical trajectories and therapeutic responses. Rather than mere epiphenomena, autoantibodies encode precise information about dominant immune pathways, organ tropism, and pathogenic mechanisms. This review synthesizes emerging evidence that autoantibody repertoires—defined by specificity, structural properties, and functional characteristics—stratify patients beyond traditional clinical taxonomy into discrete pathobiological subsets. Specific signatures such as anti-MDA5 in rapidly progressive interstitial lung disease, anti-RNA polymerase III in scleroderma renal crisis, and anti-Ro52/TRIM21 in systemic overlap syndromes illustrate how serological profiles predict outcomes with remarkable precision. Mechanistically, autoantibody pathogenicity is modulated by immunoglobulin isotype distribution, Fc glycosylation patterns, and tissue-specific receptor expression—variables that determine whether an antibody functions as a biomarker or pathogenic effector. The structural heterogeneity of autoantibodies, shaped by cytokine microenvironments and B-cell subset imprinting, creates a dynamic continuum between pro-inflammatory and regulatory states. The integration of serological, transcriptomic, and imaging data establishes a precision medicine framework: autoantibodies function simultaneously as disease classifiers and therapeutic guides. This endophenotype-driven approach is already influencing trial design and patient stratification in systemic lupus erythematosus, systemic sclerosis, and inflammatory myopathies, and is reshaping both clinical practice and scientific taxonomy in CTDs. Recognizing autoantibodies as endophenotypic determinants aligns disease classification with pathogenic mechanism and supports the transition towards immunologically informed therapeutic strategies. Full article

Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a severe form of pulmonary hypertension with poor prognosis. It most commonly arises in systemic sclerosis (SSc), followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). Its pathogenesis involves a complex interplay of immune dysregulation, chronic inflammation, endothelial injury, vascular remodeling, and fibrosis. Although vasodilators targeting the endothelin, nitric oxide, and prostacyclin pathways remain the therapeutic backbone, newer agents—including the activin signal inhibitor sotatercept and inhaled treprostinil—have expanded treatment options. Immune-targeted therapies such as glucocorticoids, cyclophosphamide, mycophenolate mofetil, rituximab, and IL-6 receptor inhibitors may benefit inflammation-dominant PAH phenotypes, while fibrotic phenotypes continue to demonstrate limited responsiveness. In addition to brain natriuretic peptide (BNP), N-terminal (NT)-proBNP and disease-specific autoantibodies, emerging biomarkers show promise for early detection, risk stratification, and personalized treatment, though validation in CTD-PAH is lacking. Advances in animal models replicating immune-mediated vascular injury and fibrosis have further improved mechanistic understanding. Despite these developments, substantial unmet needs remain, including the absence of disease-specific therapeutic strategies, limited biomarker integration into clinical practice, and a scarcity of large, well-designed trials targeting individual CTD subtypes. Addressing these gaps will be essential for improving prognosis in patients with CTD-PAH. Full article

Inorganic polyphosphate is highly conserved, critical, yet poorly understood polymer that regulates diverse cellular functions in mammals. Its importance is well established in coagulation, inflammation, mitochondrial function, and stress responses, though the molecular mechanisms for these effects remain only partly understood. Fundamental questions also persist regarding its physiological concentration, chain-length distributions, and the mechanisms that regulate its behavior in specific cellular compartments. Progress is limited by the absence of a known mammalian polyphosphate-synthesizing enzyme. Despite this, recent studies have broadened the scope of polyphosphate biology, suggesting roles in protein phase separation, ATP-independent chaperone activity, metabolic regulation, and intracellular signaling. Polyphosphate modulates the mitochondrial permeability transition pore through calcium-dependent regulation and activates factor XII in coagulation. Findings have also introduced potential connections between polyphosphate and processes such as neurodegeneration, cancer, and tissue regeneration. Despite this expanding landscape, many biological effects remain difficult to interpret due to incomplete mapping of protein targets and longstanding technical limitations in detecting and quantifying polyP. This review integrates molecular protein-interaction mechanisms with compartment-specific functions and disease physiology, providing a clearer mechanistic framework while identifying key conceptual and methodological gaps and outlining priorities for advancing polyphosphate research in mammalian systems. Full article

Background: Coffin–Siris syndrome 12 (CSS12) is a recently described neurodevelopmental disorder caused by heterozygous pathogenic variants in BICRA, a gene encoding a core subunit of the non-canonical BAF (ncBAF) chromatin-remodeling complex. The condition is characterized by developmental delay, hypotonia, hypertrichosis, and joint laxity. However, long-term data remain limited, and systemic manifestations are incompletely defined. Case Description: We report a 22-year-old male with a de novo BICRA frameshift variant, c.2479_2480delinsA (p.Ala827Thrfs*15), previously included in the original cohort reported by Barish et al. Longitudinal follow-up revealed an expanded phenotype extending beyond neurodevelopmental features. Early findings included global developmental delay, growth hormone deficiency, short stature, and joint hypermobility. In adolescence and adulthood, he developed severe intestinal dysmotility requiring total colectomy, recurrent spontaneous pneumothoraces from bilateral apical bullous disease, and portal-vein thrombosis, representing visceral and vascular complications not previously emphasized in BICRA-related disorders. The identified BICRA variant truncates the coiled-coil domain critical for BRD9/BRD4 interaction, consistent with a loss-of-function mechanism. The patient’s systemic features suggest that BICRA haploinsufficiency affects not only neurodevelopmental pathways but also smooth-muscle and connective-tissue integrity. Conclusions: This case expands the phenotypic spectrum of BICRA-related CSS12, demonstrating that visceral and vascular involvement can occur alongside neurodevelopmental and connective-tissue features. Recognition of these broader manifestations underscores the need for lifelong multidisciplinary surveillance and contributes to understanding the diverse biological roles of the ncBAF complex in human development. Full article

Accurate medical image segmentation plays a crucial role in clinical diagnosis by precisely delineating diseased tissues and organs from various medical imaging modalities. However, existing segmentation methods often fail to effectively capture low-level structural details and exhibit inconsistencies in feature connection, which may compromise diagnostic reliability. To address these limitations, this study proposes a novel Multilayer Perceptron–Transformer encoding architecture that integrates the Shift Multilayer Perceptron and Transformer mechanisms. Specifically, a SENet-based Atrous Spatial Pyramid Pooling module is designed to extract multi-scale contextual representations, while the Shift MLP refines underlying spatial features. Moreover, a channel–feature aggregation attention module is introduced to strengthen information flow between the encoder and decoder layers. Experimental results on the Automatic Cardiac Diagnostic Challenge dataset show an average Dice Similarity Coefficient (DSC) of 87.01% (83.32% for the right ventricle, 90.90% for the left ventricle, and 86.83% for the myocardium). On the Synapse multi-organ segmentation dataset, the proposed model achieves an average DSC of 79.35% and a 95% Haus Dorff Distance of 20.07 mm. These results demonstrate that MPT effectively captures both local and global anatomical structures, providing reliable support for clinical diagnosis. Full article

Objectives: To develop and validate a transthoracic lung ultrasound (TLUS)-integrated clinical nomogram for predicting pulmonary arterial hypertension (PAH) in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). Methods: This multicenter retrospective study included 550 patients with CTD-ILD from the Second Affiliated Hospital of Fujian Medical University and 169 external cases from the Xijing Hospital, Fourth Military Medical University. Patients were randomly divided into a training cohort (n = 385) and an internal validation cohort (n = 165); the external dataset served as a testing cohort. Demographic, physiological, laboratory, pulmonary function, and TLUS data were collected. Univariate and multivariate logistic regression analyses identified independent predictors of PAH, which were used to construct a nomogram model. Discrimination was assessed using receiver operating characteristic (ROC) curves and area under the curve (AUC) values. Calibration, decision curve analysis (DCA), and clinical impact curves (CIC) were performed to evaluate model accuracy and clinical utility. Results: Five independent predictors were identified: respiratory rate, diffusing capacity of the lung for carbon monoxide (DLCO% predicted), TLUS score, red blood cell (RBC) count, and brain natriuretic peptide (BNP). The model achieved excellent discrimination with AUCs of 0.952 (95% confidence interval [CI]: 0.927–0.977) in the training cohort, 0.935 (95% CI: 0.885–0.985) in the validation cohort, and 0.874 (95% CI: 0.806–0.942) in the testing cohort, outperforming individual predictors. Calibration plots showed close agreement between predicted and observed probabilities, while DCA and CIC confirmed strong clinical benefit and applicability across all thresholds. Conclusions: This TLUS-integrated nomogram provides a noninvasive and reliable tool for individualized PAH risk assessment in CTD-ILD patients. By combining ultrasound findings with physiological and laboratory markers, the model enables accurate detection of high-risk cases and may assist clinicians in optimizing surveillance and management strategies. Full article

Background/Objectives: Patients with rheumatic immune-mediated inflammatory diseases (R-IMID) require latent tuberculosis infection screening and, in case of positivity, chemoprophylaxis. Isoniazid INH remains the standard regimen, but hepatotoxicity is an underrecognized concern. To describe the characteristics of R-IMID patients developing hepatotoxicity during INH therapy and identify potential risk factors through clinical analysis and literature review. Methods: Retrospective study of 64 R-IMID who developed hepatotoxicity with INH. Mean age was 53.4 ± 10.5 years; 70.3% female. Diagnoses included spondyloarthritis/psoriatic arthritis (56.3%), rheumatoid arthritis (32.8%), systemic sclerosis (4.7%), connective tissue diseases (4.7%), and other IMIDs (3.2%). All patients showed ≥ 2 × upper limit of normality (ULN) liver enzyme elevation, 34.4% ≥ 3 ULN, 20.3% ≥ 4 ULN. Literature review (19 studies) revealed INH-related hepatotoxicity rates of 1–41%, exacerbated by concurrent methotrexate, sulfasalazine, TNF inhibitors, and prior drug-induced liver injury. Results: Hepatotoxicity was frequent when INH was combined with other hepatotoxic drugs, especially methotrexate. Conclusions: INH prophylaxis in R-IMID patients carries substantial hepatotoxic risk. Careful hepatic monitoring and individualized risk stratification are essential to prevent liver injury in immunosuppressed populations. Full article

In this study, the synergistic effects of dietary Bacillus velezensis AAHM-BV2301, silica nanoparticles (SiNPs), and chitosan (CS) on the growth performance, innate immunity, gut microbiota, and disease resistance of Asian seabass (Lates calcarifer) fingerlings were evaluated. A total of 400 fish (11.25 ± 2.12 g) were assigned to five dietary treatments for 30 days: control, BV (1 × 10⁸ CFU/kg feed), BVSiNP (1 × 10⁸ CFU/kg + 2 mg SiNP/kg), BVCS (1 × 10⁸ CFU/kg + 15 g CS/kg), and BVSiNPCS (combined additives at the same concentrations). The growth indices (WG, SGR, RGR, and FCR) significantly increased in the fish fed BVSiNPs, whereas the level of innate immunity increased across all the supplemented groups, with BVCS and BVSiNPCS having the strongest respiratory burst and lysozyme activities. The tissue-specific modulation of immune-related genes (α2M, HSP70, Mx, and C3) was most pronounced in BVSiNP-fed fish, particularly in the gills and liver. Gut microbiome profiling revealed enrichment of Cetobacterium somerae in response to BV-based treatments, whereas BVSiNPCS induced the greatest increase in microbial richness and network connectivity. Postchallenge survival against Vibrio vulnificus was significantly greater in the BV and BVSiNP groups (p < 0.05). Overall, SiNPs acted as functional enhancers of the B. velezensis probiotic, supporting improved growth, immune activation, and microbiota restructuring. These results highlight the potential of nanoparticle-integrated synbiotics for microbiome-targeted health management in aquaculture. Full article

(1) Background: Wound healing is a highly coordinated process encompassing hemostasis, inflammation, angiogenesis, keratinocyte migration, collagen deposition, and extracellular matrix remodeling. Successful repair also requires adequate nutrient and oxygen delivery through a well-developed vascular supply. Disruption of these processes can occur through aberrations in diverse biological pathways, including extracellular matrix organization, cellular adhesions, angiogenesis, and immune regulation. (2) Methods: We reviewed mechanisms of impaired tissue repair in monogenic disorders by focusing on three categories—connective tissue, hematological/immunological, and aging-related disorders—to illustrate how single-gene defects disrupt inflammation, cellular proliferation, and matrix remodeling. Additionally, we reviewed various polygenic disorders—chronic kidney disease, diabetes mellitus, hypertension, and obesity—to contrast complex multifactorial pathologies with single-gene defects. (3) Results: This review establishes that genetic impediments, despite their distinct etiologies, monogenic and polygenic disorders share critical downstream failures in the wound healing cascade. While monogenic diseases illustrate direct causal links between specific protein deficits and repair failure, polygenic diseases demonstrate how multifactorial stressors overwhelm the body’s regenerative capacity. (4) Conclusions: This review synthesizes current evidence on both monogenic diseases and polygenic contributions to impaired wound healing. These findings highlight that genetic susceptibility is a decisive factor in the ability to restore tissue homeostasis. This underscores the profound impact of genetic background on the efficacy of hemostasis, inflammation, and remodeling. Full article

The adenosine 3′,5′-cyclic monophosphate–protein kinase A (cAMP-PKA) signaling pathway is highly utilized in human physiology. It is a crucial component of development and is vital to cellular function in nearly all tissues. Indeed, genetic mutations to cAMP-PKA machinery are found in many pathologies, including multiple cancers, cardiac myxoma, neurodevelopmental disorders, and hypercortisolism. Cyclic AMP and PKA were first identified as vital components in cortisol synthesis over 50 years ago, yet the cellular mechanisms connecting PKA to cortisol production are still not well understood. This article will review evidence for PKA’s roles in adrenal gland zona fasciculata steroidogenesis and consider recent studies of the stress hormone disease adrenal Cushing’s syndrome to synthesize a current model for cAMP-PKA actions in cortisol production. Full article

Background: Asthma and atherosclerosis frequently coexist in clinical populations and share convergent immunometabolic pathways amplified by gut microbial dysbiosis. We propose the gut–lung–vascular axis as a unifying mechanistic framework connecting epithelial and endothelial inflammation providing a foundation for understanding shared inflammatory mechanisms beyond tissue-specific disease boundaries. Methods: A targeted narrative review systematically appraised clinical, experimental and multi-omics studies published over the last five years to delineate microbiota-driven pathways relevant to asthma and atherosclerosis. Particular emphasis was placed on specific microbial taxa, metabolite profiles and immunometabolic networks that connect gut dysbiosis with respiratory and cardiovascular dysfunction. Results: Across human and experimental cohorts, dysbiosis marked by depletion of short-chain fatty acids (SCFAs) producing taxa (Faecalibacterium, Roseburia, Bacteroides) and enrichment of pathobionts (Proteobacteria, Haemophilus, Moraxella, Streptococcus) promotes epithelial and endothelial barrier dysfunction, amplifying Th2/Th17-skewed inflammation and endothelial injury. Key metabolites, including SCFAs, trimethylamine N-oxide (TMAO), secondary bile acids (BA), indole/tryptophan derivatives and lipopolysaccharides (LPS), serve as molecular connectors linking gut, airway and vascular inflammation. Microbial signatures and metabolomic patterns hold emerging diagnostic and therapeutic potential, and several drug classes (e.g., statins, corticosteroids, proton-pump inhibitors (PPIs)) further modulate host–microbiota interactions. Conclusions: Shared microbial taxa and metabolite signatures in asthma and atherosclerosis support microbiota-mediated immune dysregulation along the gut–lung–vascular axis as a common pathogenic framework. Microbial and metabolite profiling may enable improved risk stratification and precise, microbiota-targeted therapies. Integrating microbiome-informed diagnostics and personalized interventions could help reduce systemic inflammation and the burden of these overlapping inflammatory diseases. Full article

Background: Bicuspid aortic valve (BAV) is the most common congenital heart defect, and its complications (namely, dilatation of the thoracic ascending aorta) raise concerns regarding the proper timing of aortic surgery. The study aim is to unravel the genetic basis of BAV and its complications through a high-throughput sequencing (HTS) approach and segregation analysis if family members were available. Methods: Fifty-two Italian BAV patients were analyzed by HTS using the Illumina MiSeq platform. Targeted sequencing of 97 genes known to be or plausibly associated with connective tissue disorders or aorthopathy was performed. Thirty-five first-degree relatives of N = 10 probands underwent mutational screening for variants identified in the index cases. Results: HTS identified 194 rare (MAF < 0.01) variants in 63 genes. Regarding previously reported genes, five NOTCH1 variants in four BAV patients, four FBN1 variants in two patients and one GATA5 variant in one patient were identified. Interestingly, among further loci, the possible contribution of PDIA2, LRP1 and CAPN2 was suggested by (a) the increased prevalence of rare genetic variants, independently from their ACMG classification in the whole BAV cohort, and (b) segregation analyses of variants identified in family members. Moreover, the present data also suggest the possible contribution of rare variants to BAV complications, specifically MYLK in aortic dilatation, CAPN2 in BAV calcification and VHL and AGGF1 in valve stenosis. Conclusions: Our results underline clinical and genetic diagnosis complexity in traits considered monogenic, such as BAV, but characterized by variability in disease phenotypic expression (incomplete penetrance), as well as the contribution of different major and modifier genes to the development of complications. Full article

Background:  Clostridioides difficile infection (CDI) remains a challenging condition, particularly in severe or recurrent cases. This study aimed to identify factors associated with recurrent CDI (rCDI), severe disease (defined by ZAR score or ESCMID criteria), death during CDI, and bloodstream infections (BSI) or candidemia within 8 weeks of CDI onset. Methods: We conducted a prospective study at an Italian university hospital that included all adult CDI cases diagnosed between November 2022 and December 2024. Statistical analyses were performed with IBM SPSS Statistics. A p-value < 0.05 was considered statistically significant in univariate analyses. For the multivariable analysis, we selected the variables that were statistically significant in the univariate analysis and considered the most clinically relevant. Results: A total of 161 CDI cases were identified. Recurrence occurred in 13%, higher than the 4% reported in a previous retrospective cohort at the same center (2013–2022). In univariate analysis, independent predictors of recurrent CDI (rCDI) were therapeutic regimens including oral vancomycin (p = 0.008; OR 6.17; 95% CI 1.36–27.97), peripheral vascular disease (PVD) (p < 0.001; OR 5.92; 95% CI 2.07–16.94), and dysphagia (p = 0.034; OR 4.61; 95% CI 1.25–17.07), whereas fidaxomicin use was associated with a protective effect (p = 0.016; OR 0.17; 95% CI 0.04–0.78). In multivariable analysis, oral vancomycin use (p = 0.008; OR 15.03) and peripheral vascular disease (p = 0.002; OR 7.27) remained independently associated with rCDI. Overall, 15 of 161 patients (9.3%) died during the CDI episode (either presenting CDI or rCDI), with all deaths directly attributable to CDI. Mortality during CDI was associated with age > 77 years (median value of the study population), transfer from a nursing home or long-term care facility within the previous 3 months, lymphoma, hematological malignancy, peripheral vascular disease, connective tissue disease, immobilization syndrome, dysphagia, elevated lactate levels (>1 mmol/L), septic shock, severe or severe-complicated CDI according to ESCMID criteria, severe-complicated CDI according to ESCMID criteria, leukocytosis (WBC > 15,000/mm³) during CDI, ZAR score ≥ 2, concomitant BSI, and concomitant pneumonia. During follow-up, 11 of 127 (8.7%) patients developed a BSI. BSI was associated with corticosteroid use and osteomyelitis. Only four patients developed candidemia due to Candida albicans during follow-up. Conclusions: Our study confirms that Clostridioides difficile infection remains a major clinical challenge, particularly due to its high recurrence rate and the burden of severe forms. The evidence strongly supports the preferential use of fidaxomicin, which should now be regarded as the standard of reference in clinical practice. Full article