Search Results (631)

Background: Pulmonary fibrosis (PF), the end-stage manifestation of interstitial lung disease, is defined by excessive extracellular matrix deposition and alveolar destruction. Activated fibroblasts, the primary matrix producers, rely heavily on dysregulated glucose metabolism for their activation. While Salt Inducible Kinase 2 (SIK2) regulates glycolytic pathways in oncogenesis, its specific contributions to fibroblast activation and therapeutic potential in PF pathogenesis remain undefined. This study elucidates the functional role of SIK2 in PF and assesses its viability as a therapeutic target. Methods: SIK2 expression/localization in fibrosis was assessed by Western blot and immunofluorescence. Fibroblast-specific Sik2 KO mice evaluated effects on bleomycin-induced fibrosis. SIK2’s role in fibroblast activation and glucose metabolism impact (enzyme expression, metabolism assays, metabolites) were tested. SIK2 inhibitors were screened and evaluated therapeutically in fibrosis models. Results: It demonstrated significant SIK2 upregulation, specifically within activated fibroblasts of fibrotic lungs from both PF patients and murine models. Functional assays demonstrated that SIK2 is crucial for fibroblast activation, proliferation, and migration. Mechanistically, SIK2 enhances fibroblast glucose metabolism by increasing the expression of glycolysis-related enzymes. Additionally, this study demonstrated that the SIK2 inhibitor YKL06-061 effectively inhibited PF in both bleomycin and FITC-induced PF mouse models with the preliminary safety profile. Furthermore, we identified a novel therapeutic application for the clinically approved drug fostamatinib, demonstrating it inhibits fibroblast activation via SIK2 targeting and alleviates PF in mice. Conclusions: Our findings highlight SIK2 as a promising therapeutic target and provide compelling preclinical evidence for two distinct anti-fibrotic strategies with significant potential for future PF treatment. Full article

Background: Patients with mastocytosis may present with exacerbated respiratory symptoms and lung diseases resulting from mast cell mediator release. However, their prevalence and severity level remain under debate. The study aims to analyze the prevalence of respiratory symptoms and the usefulness of lung function tests like spirometry, diffusing capacity of the lung for carbon monoxide (DLCO), and high-resolution computed tomography (HRCT) of the chest in mastocytosis patients presenting with dyspnea, cough, and exercise intolerance. Methods: We included 104 patients with mastocytosis and 71 healthy controls. Data collection encompassed patient interview, clinical examination, spirometry, DLCO, and chest HRCT. Diagnosis of mastocytosis included bone marrow biopsies and serum tryptase measurements. Results: Compared to controls, patients with mastocytosis exhibited significantly lower values in FEV1/VC ratio, absolute DLCO/VA, predicted DLCO/VA, absolute DLCOcSB, and predicted DLCOcSB (p < 0.001). Commonly reported respiratory symptoms included dyspnea (36.5%), chest tightness (22.1%), and wheezing (9.6%). Airway obstruction was identified in 7.7% of patients; however, it appeared to be independent of the mastocytosis subtype. A decreased DLCO/VA ratio was observed in 4.8% of patients, but HRCT did not reveal any evidence of underlying lung disease. Conclusions: Mastocytosis appears to be a risk factor for the occurrence and exacerbation of respiratory symptoms. However, airway obstruction and impairment of the alveolar–capillary membrane seem to occur independently of the clinical subtype of mastocytosis. Additionally, the causal relationship between pulmonary involvement, mast cell infiltration of the alveolar–capillary membrane, and the systemic circulation of mast cell mediators remains unclear and requires further research. Full article

Malignant mediastinal tumors are a group representing some of the most demanding oncological challenges for early, multi-level, and successful management. The timely identification of any suspicious clinical symptomatology is urgent in achieving an accurate, staged histological diagnosis, in order to follow up with an equally detailed medical therapeutic plan (interventional or not) and determine the principal goals regarding efficient overall treatment in these patients. We report a case of a 24-year-old male patient with an incident-free prior medical history. An initial chest X-ray was performed after the patient reported short-term, consistent moderate chest pain symptomatology, early work fatigue, and shortness of breath. The following imaging procedures (chest CT, PET-CT) indicated the presence of an anterior mediastinal mass (meas. ~11 cm × 10 cm × 13 cm, SUV: 8.7), applying additional pressure upon both right heart chambers. The Alpha-Fetoprotein (aFP) blood levels had exceeded at least 50 times their normal range. Two consecutive diagnostic attempts with non-specific histological results, a negative-for-malignancy fine-needle aspiration biopsy (FNA-biopsy), and an additional tumor biopsy, performed via mini anterior (R) thoracotomy with “suspicious” cellular gatherings, were performed elsewhere. After admission to our department, an (R) Video-Assisted Thoracic Surgery (VATS) was performed, along with multiple tumor biopsies and moderate pleural effusion drainage. The tumor’s measurements had increased to DMax: 16 cm × 9 cm × 13 cm, with a severe degree of atelectasis of the Right Lower Lobe parenchyma (RLL) and a pressure-displacement effect upon the Superior Vena Cava (SVC) and the (R) heart sinus, based on data from the preoperative chest MRA. The histological report indicated elements of a combined, non-seminomatous germ-cell mediastinal tumor, posthuberal-type teratoma, and embryonal carcinoma. The imminent chemotherapeutic plan included a “BEP” (Bleomycin^®/Cisplatin^®/Etoposide^®) scheme, which needed to be modified to a “VIP” (Cisplatin^®/Etoposide^®/Ifosfamide^®) scheme, due to an acute pulmonary embolism incident. While the aFP blood levels declined, even reaching normal measurements, the tumor’s size continued to increase significantly (DMax: 28 cm × 25 cm × 13 cm), with severe localized pressure effects, rapid weight loss, and a progressively worsening clinical status. Thus, an emergency surgical intervention took place via median sternotomy, extended with a complementary “T-Shaped” mini anterior (R) thoracotomy. A large, approx. 4 Kg mediastinal tumor was extracted, with additional RML and RUL “en-bloc” segmentectomy and partial mediastinal pleura decortication. The following histological results, apart from verifying the already-known posthuberal-type teratoma, indicated additional scattered small lesions of combined high-grade rabdomyosarcoma, chondrosarcoma, and osteosarcoma, as well as numerous high-grade glioblastoma cellular gatherings. No visible findings of the previously discovered non-seminomatous germ-cell and embryonal carcinoma elements were found. The patient’s postoperative status progressively improved, allowing therapeutic management to continue with six “TIP” (Cisplatin^®/Paclitaxel^®/Ifosfamide^®) sessions, currently under his regular “follow-up” from the oncological team. This report underlines the importance of early, accurate histological identification, combined with any necessary surgical intervention, diagnostic or therapeutic, as well as the appliance of any subsequent multimodality management plan. The diversity of mediastinal tumors, especially for young patients, leaves no place for complacency. Such rare examples may manifest, with equivalent, unpredictable evolution, obliging clinical physicians to stay constantly alert and not take anything for granted. Full article

Background and Clinical Significance: Antisynthetase syndrome (ASyS) is a rare autoimmune entity defined by the presence of anti-aminoacyl-t ribonucleic acid (RNA) synthetase autoantibodies and classically associated with a triad of interstitial lung disease (ILD), inflammatory myopathy, and arthritis. Additional clinical features may include Raynaud’s phenomenon and “mechanic’s hands”. Among antisynthetase antibodies, anti-PL-12 is notably associated with predominant or isolated ILD and may occur in the absence of clinically evident myositis, thereby complicating timely diagnosis. Case Presentation: We are presenting a 45-year-old non-smoking female patient with a prior diagnosis of seronegative rheumatoid arthritis (RA) who developed progressive dyspnea, dry cough, and sicca symptoms. High-resolution computed tomography revealed a nonspecific interstitial pneumonia (NSIP) pattern. Despite normal creatine kinase and lactate dehydrogenase levels, serological work-up revealed positive anti-PL-12 and anti-Ro52 antibodies, supporting a diagnosis of antisynthetase syndrome without myositis, fulfilling the diagnostic criteria for ASyS per Connors and Solomon. Treatment with corticosteroids and cyclophosphamide induced clinical and functional respiratory improvement, while azathioprine was initiated for maintenance. Conclusions: This case underscores the clinical heterogeneity of antisynthetase syndrome and highlights the diagnostic challenge posed by anti-PL-12–associated ILD in the absence of myositis. Importantly, it demonstrates that in patients with pre-existing rheumatologic diagnoses, the emergence of atypical pulmonary manifestations warrants repeat serologic evaluation to assess ASyS and other autoimmune conditions. Early diagnosis and immunosuppressive treatment are essential to optimize outcomes. Full article

Extra-pulmonary tuberculosis (EPTB) can affect any organ of the body, producing a wide variety of clinical manifestations that make the diagnosis and treatment of EPTB challenging. The optimum treatment varies depending on the site of EPTB, its severity, and response to treatment. There is often uncertainty about the best management practices, with a significant departure from national guidelines. This study aims to identify gaps and barriers in adhering to the national guidelines for the diagnosis and treatment of EPTB. We included 433 patients having EPTB and followed up at predefined intervals of 2 months, 6 months, 9 months, and 12 months. Questionnaire-based interviews of the treating physician and the patients in different departments were conducted. For confirmatory diagnosis, heavy dependence on clinical-radiological diagnosis without microbiological support was observed, which is a deviation from National Tuberculosis Elimination Programme (NTEP) guidelines and raises concerns about the potential for misdiagnosis and overtreatment. Apart from patient delays, long health system delays in EPTB were observed. The median patient delay, health system delay, and total treatment delay times were 4.2, 4, and 10.1 weeks, respectively. To enhance EPTB diagnosis and management, there is a pressing need for improved access to microbiological testing, enhanced physician training on adherence to NTEP guidelines, and greater utilisation of imaging and histopathological techniques. Full article

Increased epithelial and endothelial permeability, along with dysregulated inflammatory responses, are key aspects of acute respiratory distress syndrome (ARDS) pathophysiology, which not only impact the lungs but also contribute to detrimental organ crosstalk with distant organs, ultimately leading to multiple organ dysfunction syndrome (MODS)—the primary cause of morbidity and mortality in patients with lung injury (LI) and ARDS. It is predominantly manifested by hypoxemic respiratory failure and bilateral pulmonary infiltrates, which cannot be fully attributed to cardiac failure or hypervolemia, but rather to alveolo-capillary barrier dysfunction, dysregulated systemic and pulmonary inflammation, immune system abnormalities, and mechanical stimuli-related responses. However, these pathological features are not uniform among patients with ARDS, as distinct subphenotypes with unique biological, clinical, physiological, and radiographic characteristics have been increasingly recognized in recent decades. The severity of ARDS, clinical outcomes, mortality, and efficacy of applied therapeutic measures appear significant depending on the respective phenotype. Acknowledging the heterogeneity of ARDS and defining distinct subphenotypes could significantly modify therapeutic strategies, enabling more precise and targeted treatments. To address these issues, a comprehensive literature search was conducted in PubMed using predefined keywords related to ARDS pathophysiology, subphenotypes, and personalized therapeutic approaches. Optimizing the identification and characterization of discrete ARDS subphenotypes—based on clinical, biological, physiological, and radiographic criteria—will deepen our understanding of ARDS pathophysiology, promote targeted recruitment in prospective clinical studies to define patient clusters with heterogeneous therapeutic responses, and support the shift toward individualized treatment strategies. Full article

Background: Staphylococcus aureus is a significant pathogen causing both local and systemic infections in children, with deep tissue involvement leading to severe complications. This study aimed to assess clinical manifestations and identify risk factors for deep tissue involvement in pediatric S. aureus infections. Methods: All children between 1 month and 18 years who had S. aureus growth in blood, pus, or joint fluid culture were included. Results: A total of 61 patients (median age 55 months) were included, with 22.9% having deep tissue infections. Osteoarticular infections, pyomyositis, and pulmonary involvement were common. Deep-seated infections were significantly associated with community-acquired infections and positive hemocultures after 72 h (p < 0.01). Laboratory results showed significantly higher levels of C-reactive protein, sedimentation rate, D-dimer, and fibrinogen in the group with deep-seated infections (p = 0.02, p = 0.018, p = 0.01, and p = 0.015, respectively). The decision tree model showed that the first indicator of deep-seated infection was a D-dimer level above 1.15 mg/L, followed by a fibrinogen level above 334 mg/dL. Conclusions: Deep-seated S. aureus infections are more frequently associated with community-acquired cases, persistent hemoculture positivity, and methicillin-susceptible Staphylococcus aureus (MSSA) strains. Additionally, elevated D-dimer and fibrinogen levels may serve as valuable markers for identifying deep-seated infections in pediatric patients. Full article

Systemic sclerosis (SSc) is a heterogeneous disease characterized by vascular alterations, immune dysregulation, and fibrosis. Solid evidence supports the hypothesis that endothelial dysfunction is the key player in SSc vascular injury and a critical factor concurring to the initiation of SSc pathogenesis. This narrative review reports on persistent endothelial dysfunction, resulting from oxidative stress, autoimmunity, and impaired vascular repair, in the course of SSc, and how it can trigger and sustain fibrotic remodeling of various organs. In this paper, we also analyze the impact on SSc of impaired angiogenesis and vasculogenesis, diminished endothelial progenitor cell function, and endothelial-to-mesenchymal transition, which can collectively disrupt vascular homeostasis and promote myofibroblast activation. These pathologic events underlie the hallmark clinical manifestations, i.e., Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. The review highlights how recognizing SSc as a paradigm of systemic endothelial dysfunction may reframe our understanding of its physiopathology, modify current therapeutic strategies, and unveil new therapeutic targets. Full article

Aging is a multifaceted biological process characterized by a progressive decline in cellular function and physiological resilience, increasing the risk of multiple chronic conditions. Chronic lung diseases frequently manifest within the aging population and are closely intertwined with systemic dysfunctions across cardiovascular, musculoskeletal, and neurological systems. In this review, we explore the biological mechanisms linking aging, multiple chronic conditions patterns, and chronic lung disease, with a particular focus on inflammaging and cellular aging. We also highlight shared pathological pathways such as oxidative stress, mitochondrial dysfunction, and the dysregulation of repair processes that underlie both natural aging and the accelerated aging seen in chronic lung disease. Additionally, we discuss the systemic impact of multiple chronic conditions on patient outcomes, including increased frailty, diminished physical capacity, cognitive impairment, and elevated mortality risk. This review advocates for a comprehensive, patient-centered approach that combines early detection, personalized pharmacological therapies targeting inflammatory and senescent pathways, and non-pharmacological interventions such as pulmonary rehabilitation, exercise, and dietary optimization. Emerging therapeutics, including senolytics and anti-inflammatory agents, present promising avenues for mitigating age-related lung decline and managing multiple chronic conditions. Full article

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition marked by persistent airflow limitation and is currently the fourth leading cause of death worldwide, accounting for 3.5 million deaths in 2021. While its physical manifestations such as dyspnea, chronic cough, and sputum production are well known, its psychological impact, particularly the high prevalence of depression among patients, remains under-recognized. Objectives: This narrative review aims to summarize the existing data on the association between COPD and depression, analyze their pathophysiological connections, explore treatment possibilities, and highlight the interrelationships between these conditions. Methods: A non-systematic literature search was conducted using PubMed, Scopus, and Google Scholar. Studies, reviews, and key publications addressing the relationship between COPD and depression were selected based on clinical relevance. Findings were synthesized thematically to provide a comprehensive and critical overview. Results: Depression in patients with COPD is linked to worse quality of life, increased functional impairment, higher suicide risk, and poorer adherence to treatment. Contributing mechanisms include chronic systemic inflammation, hypoxemia, oxidative stress, and psychosocial risk factors such as low educational level, socioeconomic disadvantage, and comorbidities. Despite evidence of this strong association, treatment strategies remain limited and underutilized, and no unified approach has yet been established. Conclusions: Depression represents a major comorbidity in COPD that exacerbates both disease burden and patient suffering. Further research is essential to clarify the underlying mechanisms and to develop integrated therapeutic approaches. Enhancing our understanding and management of this comorbidity holds promise for significantly improving patient outcomes and overall quality of life. Full article

Tricuspid regurgitation (TR) represents a significant, often silently progressing, valvular heart disease with historically suboptimal management due to perceived high surgical risks. Transcatheter tricuspid valve interventions (TTVI) offer a promising, less invasive therapeutic avenue. Central to the success of TTVI is Right Ventricular Reverse Remodelling (RVRR), defined as an improvement in RV structure and function, which strongly correlates with enhanced patient survival. The right ventricle (RV) undergoes complex multi-scale biomechanical maladaptations, progressing from adaptive concentric to maladaptive eccentric hypertrophy, coupled with increased stiffness and fibrosis. Molecular drivers of this pathology include early failure of antioxidant defenses, metabolic shifts towards glycolysis, and dysregulation of microRNAs. Accurate RV function assessment necessitates advanced imaging modalities like 3D echocardiography, Cardiac Magnetic Resonance Imaging (CMR), and Computed Tomography (CT), along with strain analysis. Following TTVI, RVRR typically manifests as a biphasic reduction in RV volume overload, improved myocardial strain, and enhanced RV-pulmonary arterial coupling. Emerging molecular biomarkers alongside advanced imaging-derived biomechanical markers like CT-based 3D-TAPSE and RV longitudinal strain, are proving valuable. Artificial intelligence (AI) and machine learning (ML) are transforming prognostication by integrating diverse clinical, laboratory, and multi-modal imaging data, enabling unprecedented precision in risk stratification and optimizing TTVI strategies. Full article

Objectives: Deep learning-based artificial intelligence (AI) tools have been gradually used to detect and segment pulmonary nodules in clinical practice. This study aimed to assess the diagnostic performance of quantitative measures derived from a commercially available AI software for predicting the invasiveness of pulmonary adenocarcinomas that manifested as pure ground-glass nodules (pGGNs) on low-dose CT (LDCT) in lung cancer screening. Methods: A total of 388 pGGNs were consecutively enrolled and divided into a training cohort (198 from center 1 between February 2019 and April 2022), testing cohort (99 from center 1 between April 2022 and March 2023), and external validation cohort (91 from centers 2 and 3 between January 2021 and August 2023). The automatically extracted quantitative measures included diameter, volume, attenuation, and mass. The diameter was also manually measured by radiologists. The agreement of diameter between AI and radiologists was evaluated by intra-class correlation coefficient (ICC) and Bland–Altman method. The diagnostic performance was evaluated by the area under curve (AUC) of receiver operating characteristic curve. Results: The ICCs of diameter between AI and radiologists were from 0.972 to 0.981 and Bland–Altman biases were from −1.9% to −2.3%. The mass showed the highest AUCs of 0.915 (0.867–0.950), 0.913 (0.840–0.960), and 0.893 (0.810–0.948) in the training, testing, and external validation cohorts, which were higher than those of diameters of radiologists and AI, volume, and attenuation (all p < 0.05). Conclusions: The automated measurement of pGGNs diameter using the AI software demonstrated comparable accuracy to that of radiologists on LDCT images. Among the quantitative measures of diameter, volume, attenuation, and mass, mass was the most optimal predictor of invasiveness in pulmonary adenocarcinomas on LDCT, which might be used to assist clinical decision of pGGNs during lung cancer screening. Full article

Background/Objectives: Pulmonary lymphangitic carcinomatosis (PLC) is a rare, aggressive manifestation of metastatic cancer characterized by lymphatic infiltration of the lungs, typically indicating advanced disease and poor prognosis. Methods: This comprehensive narrative review evaluates the role of [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) imaging in assessing PLC. Results: Current evidence demonstrates that [18F]FDG PET/CT achieves high diagnostic accuracy, with sensitivity and specificity ranging from 86 to 97% and 84 to 100%, respectively, particularly when employing semiquantitative metrics such as peritumoral standardized uptake value (SUVmax) thresholds (e.g., ≥2.1). PET/CT surpasses high-resolution computed tomography (HRCT) in distinguishing PLC from mimics like pulmonary sarcoidosis by identifying distinct metabolic patterns: bronchovascular hypermetabolism in PLC versus subpleural nodular uptake in sarcoidosis. Prognostically, metabolic tumor burden (e.g., SUVmax × involved lobes) and novel cPLC classifications (localized to the ipsilateral or contralateral lung) independently predict progression-free survival. However, challenges persist, including non-specific tracer uptake in inflammatory conditions and variability in SUV measurements due to technical factors. Emerging digital PET/CT systems, with enhanced spatial resolution, may improve the detection of focal PLC and reduce false negatives. While [18F]FDG PET/CT is invaluable for whole-body staging, therapeutic monitoring and biopsy guidance, the standardization of protocols and multicenter validation of prognostic models are critical for clinical integration. Future research should explore novel tracers (e.g., PSMA for prostate cancer-related PLC) and machine learning approaches to refine diagnostic and prognostic accuracy. Conclusions: This review underscores the role and the transformative potential of [18F]FDG PET/CT in PLC management while advocating for rigorous standardization to maximize its clinical utility. Full article

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder caused by pathogenic variants in ENG (HHT1) and ACVRL1 (HHT2), with distinct phenotypic expressions. Background/Objectives: This study investigates the genotype–phenotype correlations, including comparing the quality of life by phenotype, conducting a cardiovascular risk assessment, and evaluating the impact of mutation type on its clinical manifestations and prognosis. Methods: A cross-sectional study was conducted on 85 HHT patients, stratified into HHT1 (ENG, n = 43) and HHT2 (ACVRL1, n = 42). Their clinical and biochemical parameters, arteriovenous malformations (AVMs), epistaxis severity, quality of life, and cardiovascular risk were assessed. Genetic variants were classified as truncating or non-truncating. The statistical analyses included logistic regression and survival analysis. Results: The onset of epistaxis occurred earlier in HHT1 (log-rank p = 0.011), whereas its severity (p = 0.006) and iron deficiency were greater in HHT2 (p = 0.043). Pulmonary AVMs were significantly more frequent in HHT1 (58.1% vs. 9.5%, p < 0.01), contributing to a potential decrease in survival, despite the greater hemorrhagic burden in HHT2. Truncating mutations were independently associated with anemia (p < 0.05). Cardiovascular risk (measured using the SCORE2 scale) was low to moderate, and quality of life (measured using the EQ-5D-5L scale) was most impaired in patients with severe epistaxis (p = 0.031) or anemia (p = 0.026). Truncating mutations influence the severity of anemia independently of genotype. Limitations: The principal limitations include the small sample size and the bias generated by this being a paper based on another prospective study with a methodology designed for different objectives. Conclusions: These findings underscore the need for personalized management strategies based on genotype and mutation type. Further prospective studies are warranted to validate these associations and optimize the risk stratification in HHT. Full article

Thyroid hormones (THs) play a central role in cardiovascular and metabolic regulation, influencing lipid metabolism, insulin sensitivity and resting energy expenditure. Inherited disorders of impaired sensitivity to THs—including resistance to thyroid hormone alpha (RTHα) and beta (RTHβ), monocarboxylate transporter 8 (MCT8) deficiency and selenoprotein deficiency—lead to complex, multisystemic clinical features. Although these conditions are rare, with RTHβ being the most common and affecting about 1 in 20,000 newborns, they share clinical features with more prevalent thyroid disorders, such as hypothyroidism and hyperthyroidism, as well as neurological manifestations including muscle wasting and spasticity. These conditions present abnormal patterns of thyroid function and are associated with tissue-specific comorbidities such as arrhythmias, heart failure, dyslipidemia, hepatic steatosis, insulin resistance, and metabolic syndrome. To date, no targeted or controlled studies have evaluated the impact of lifestyle modifications in these patient populations. Therefore, this narrative review proposes plausible management strategies based on pathophysiological insights into the effects of thyroid hormones on target organs, combined with clinical reasoning and evidence extrapolated from related disorders. Physical exercise and diet may complement pharmacological treatments (e.g., levothyroxine or TRIAC) to improve cardiovascular and metabolic outcomes. In RTHβ, aerobic exercise enhances cardiovascular health, while a Mediterranean diet supports lipid control and glycemic parameters. In RTHα, physical exercise may aid neuromotor development, and a fluid-rich, fiber-moderated diet can alleviate constipation. In MCT8 deficiency, physiotherapy may improve mobility and relieve contractures, while nutritional support (e.g., feeding tube, gastrostomy) can be necessary to tackle feeding difficulties and reduce pulmonary complications. In selenoprotein deficiency, low-to-moderate physical exercise and an antioxidant-rich diet may protect against oxidative stress at several tissue levels. Although quantitative evidence is limited, this narrative review synthesizes current insights, providing a meaningful basis for future validation and research. Full article