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Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.
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Alérgenos , Interleucina-33 , Proteínas de Unión a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Animales , Caspasa 1/metabolismo , Inflamación , Interleucina-1beta/metabolismo , Interleucina-33/genética , Interleucina-33/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Péptido Hidrolasas/metabolismo , Gránulos de EstrésRESUMEN
Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic ß-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-ß1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.
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Carcinoma Hepatocelular , Progresión de la Enfermedad , Elasticidad , Matriz Extracelular , Cirrosis Hepática , Neoplasias Hepáticas , Animales , Humanos , beta Catenina/metabolismo , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Proliferación Celular , Colágeno/química , Colágeno/metabolismo , Simulación por Computador , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Matriz Extracelular/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Integrina beta1/metabolismo , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Invasividad Neoplásica , Viscosidad , Proteínas Señalizadoras YAP/metabolismo , Cirrosis Hepática/complicaciones , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patologíaRESUMEN
BACKGROUND: Abnormal glycemic variability is common in the intensive care unit (ICU) and is associated with increased in-hospital mortality and major adverse cardiovascular events, but little is known about whether adverse outcomes are partly mediated by ventricular arrhythmias (VA). We aimed to explore the association between glycemic variability and VA in the ICU and whether VA related to glycemic variability mediate the increased risk of in-hospital death. METHODS: We extracted all measurements of blood glucose during the ICU stay from The Medical Information Mart for Intensive Care IV (MIMIC-IV) database version 2.0. Glycemic variability was expressed by the coefficient of variation (CV), which was calculated by the ratio of standard deviation (SD) and average blood glucose values. The outcomes included the incidence of VA and in-hospital death. The KHB (Karlson, KB & Holm, A) is a method to analyze the mediation effect for nonlinear models, which was used to decompose the total effect of glycemic variability on in-hospital death into a direct and VA-mediated indirect effect. RESULTS: Finally, 17,756 ICU patients with a median age of 64 years were enrolled; 47.2% of them were male, 64.0% were white, and 17.8% were admitted to the cardiac ICU. The total incidence of VA and in-hospital death were 10.6% and 12.8%, respectively. In the adjusted logistic model, each unit increase in log-transformed CV was associated with a 21% increased risk of VA (OR 1.21, 95% CI: 1.11-1.31) and a 30% increased risk (OR 1.30, 95% CI: 1.20-1.41) of in-hospital death. A total of 3.85% of the effect of glycemic variability on in-hospital death was related to the increased risk of VA. CONCLUSION: High glycemic variability was an independent risk factor for in-hospital death in ICU patients, and the effect was caused in part by an increased risk of VA.
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Glucemia , Enfermedad Crítica , Humanos , Masculino , Persona de Mediana Edad , Femenino , Mortalidad Hospitalaria , Arritmias Cardíacas , Bases de Datos FactualesRESUMEN
INTRODUCTION: Drug-induced QT interval prolongation has been reported to be related to life-threatening polymorphic ventricular tachycardia (torsade de pointes). Proton pump inhibitors (PPIs) are prescribed widely for hospitalized patients; the QT interval prolongation and torsade de pointes caused by PPIs were reported. We conducted a study to determine the association between PPI treatment and QT interval prolongation in critically ill patients. METHODS: This study included patients with electrocardiography (ECG) reports from the Medical Information Mart for Intensive Care III database (MIMIC-III). Patients younger than 18 years, missing baseline laboratories and with QT interval prolongation before intensive care unit (ICU) admission were excluded. The end point was the diagnosis of QT interval prolongation reported by ECG. RESULTS: This study included 24,512 ICU patients. Of them, 11,327 patients were treated with PPIs, 4181 with histamine 2 receptor antagonists (H2RAs) and 6351 without acid suppression therapy (non-AST); the incidence of QT interval prolongation were 8.5%, 3.3% and 3.4% respectively. After adjustment for demographics, electrolytes, comorbidities and medications, PPIs were associated a higher risk of QT interval prolongation compared with H2RAs (OR 1.66, 95% CI 1.36 - 2.03) and non-AST (OR 1.54, 95% CI 1.31 - 1.82), while there was not significant difference between H2RAs and non-AST (OR 0.93, 95% CI 0.73 - 1.17). In the propensity score matching population, the results were consistent. Pantoprazole (OR 2.14, 95% CI 1.52 - 3.03) and lansoprazole (OR 1.80, 95% CI: 1.18 - 2.76) showed a higher QT prolongation risk than omeprazole. Several drugs caused higher QT prolongation risk when used in combination with PPIs. CONCLUSION: In ICU patients, the association between PPI prescription and increased risk of QT interval prolongation was independent of known QT-prolonging factors; pantoprazole and lansoprazole had a higher risk compared with omeprazole. The combination of PPIs and other QT-prolonging drugs should be avoided.
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Inflammatory bowel disease (IBD) comprises chronic relapsing disorders of the gastrointestinal tract characterized pathologically by intestinal inflammation and epithelial injury. Here, we uncover a function of extracellular matrix protein 1 (ECM1) in promoting the pathogenesis of human and mouse IBD. ECM1 was highly expressed in macrophages, particularly tissue-infiltrated macrophages under inflammatory conditions, and ECM1 expression was significantly induced during IBD progression. The macrophage-specific knockout of ECM1 resulted in increased arginase 1 (ARG1) expression and impaired polarization into the M1 macrophage phenotype after lipopolysaccharide (LPS) treatment. A mechanistic study showed that ECM1 can regulate M1 macrophage polarization through the granulocyte-macrophage colony-stimulating factor/STAT5 signaling pathway. Pathological changes in mice with dextran sodium sulfate-induced IBD were alleviated by the specific knockout of the ECM1 gene in macrophages. Taken together, our findings show that ECM1 has an important function in promoting M1 macrophage polarization, which is critical for controlling inflammation and tissue repair in the intestine.
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Proteínas de la Matriz Extracelular/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Activación de Macrófagos/fisiología , Macrófagos/metabolismo , Animales , Arginasa/metabolismo , Modelos Animales de Enfermedad , Proteínas de la Matriz Extracelular/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Enfermedades Inflamatorias del Intestino/patología , Intestinos/patología , Lipopolisacáridos/farmacología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Ratones , Ratones Noqueados , Factor de Transcripción STAT5/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND AND AIMS: Older patients with obesity/type II diabetes mellitus frequently present with advanced NASH. Whether this is due to specific molecular pathways that accelerate fibrosis during aging is unknown. Activation of the Src homology 2 domain-containing collagen-related (Shc) proteins and redox stress have been recognized in aging; however, their link to NASH has not been explored. APPROACH AND RESULTS: Shc expression increased in livers of older patients with NASH, as assessed by real time quantitative PCR (RT-qPCR) or western blots. Fibrosis, Shc expression, markers of senescence, and nicotinamide adenine dinucleotide phosphate, reduced form oxidases (NOXs) were studied in young/old mice on fast food diet (FFD). To inhibit Shc in old mice, lentiviral (LV)-short hairpin Shc versus control-LV were used during FFD. For hepatocyte-specific effects, floxed (fl/fl) Shc mice on FFD were injected with adeno-associated virus 8-thyroxine-binding globulin-Cre-recombinase versus control. Fibrosis was accelerated in older mice on FFD, and Shc inhibition by LV in older mice or hepatocyte-specific deletion resulted in significantly improved inflammation, reduction in senescence markers in older mice, lipid peroxidation, and fibrosis. To study NOX2 activation, the interaction of p47phox (NOX2 regulatory subunit) and p52Shc was evaluated by proximity ligation and coimmunoprecipitations. Palmitate-induced p52Shc binding to p47phox , activating the NOX2 complex, more so at an older age. Kinetics of binding were assessed in Src homology 2 domain (SH2) or phosphotyrosine-binding (PTB) domain deletion mutants by biolayer interferometry, revealing the role of SH2 and the PTB domains. Lastly, an in silico model of p52Shc/p47phox interaction using RosettaDock was generated. CONCLUSIONS: Accelerated fibrosis in the aged is modulated by p52Shc/NOX2. We show a pathway for direct activation of the phagocytic NOX2 in hepatocytes by p52Shc binding and activating the p47phox subunit that results in redox stress and accelerated fibrosis in the aged.
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Envejecimiento/metabolismo , NADPH Oxidasa 2/fisiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Animales , Hepatocitos/metabolismo , Humanos , Cirrosis Hepática/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteínas Adaptadoras de la Señalización Shc/antagonistas & inhibidores , Proteínas Adaptadoras de la Señalización Shc/fisiología , Dominios Homologos srcRESUMEN
T-follicular helper (TFH) cells are a subset of CD4+ helper T cells that help germinal center (GC) B-cell differentiation and high-affinity antibody production during germinal center reactions. Whether important extracellular molecules control TFH differentiation is not fully understood. Here, we demonstrate that a secreted protein extracellular matrix protein 1 (ECM1) is critical for TFH differentiation and antibody response. A lack of ECM1 inhibited TFH cell development and impaired GC B-cell reactions and antigen-specific antibody production in an antigen-immunized mouse model. ECM1 was induced by IL-6 and IL-21 in TFH cells, promoting TFH differentiation by down-regulating the level of STAT5 phosphorylation and up-regulating Bcl6 expression. Furthermore, injection of recombinant ECM1 protein into mice infected with PR8 influenza virus promoted protective immune responses effectively, by enhancing TFH differentiation and neutralizing antibody production. Collectively, our data identify ECM1 as a soluble protein to promote TFH cell differentiation and antibody production.
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Formación de Anticuerpos , Linfocitos B/inmunología , Diferenciación Celular/inmunología , Proteínas de la Matriz Extracelular/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Linfocitos B/citología , Diferenciación Celular/genética , Proteínas de la Matriz Extracelular/genética , Virus de la Influenza A/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucinas/genética , Interleucinas/inmunología , Ratones , Ratones Noqueados , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/inmunología , Linfocitos T Colaboradores-Inductores/citologíaRESUMEN
The mobility and fate of Cd in soil are mainly controlled by active substances such as iron minerals and organic matter. Iron minerals and organic matter often coexist in the form of iron-organic associations (IOA), which have large specific surface areas and many functional groups, potentially affecting Cd adsorption. However, little is known about Cd adsorption by IOA. This study investigated Cd adsorption by the synthetic IOA under different conditions. The results indicate Cd adsorption increased with the increasing amount of IOA, while the adsorption efficiency decreased gradually. pH significantly affects Cd adsorption, because the Cd speciation and the surface charge of IOA changed under different pH conditions. Under alkaline condition, part of Cd would form hydroxide precipitate, facilitating Cd adsorption by IOA. The composition of organic matter in IOA didn't significantly affect Cd adsorption.
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Hierro , Contaminantes del Suelo , Adsorción , Cadmio , Minerales , SueloRESUMEN
BACKGROUND & AIMS: Activation of TGFB (transforming growth factor ß) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers. METHODS: We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Δhep). ECM1 or soluble TGFBR2 (TGFB receptor 2) were expressed in livers of mice after injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy livers were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with αv integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Δhep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. CONCLUSIONS: ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.
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Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Proteínas de la Matriz Extracelular/metabolismo , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática Experimental/prevención & control , Hígado/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Tetracloruro de Carbono , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Proteínas de la Matriz Extracelular/deficiencia , Proteínas de la Matriz Extracelular/genética , Células Estrelladas Hepáticas/patología , Hepatitis Alcohólica/metabolismo , Hepatitis Alcohólica/patología , Hepatitis Viral Humana/metabolismo , Hepatitis Viral Humana/patología , Humanos , Hígado/patología , Cirrosis Hepática Alcohólica/metabolismo , Cirrosis Hepática Alcohólica/patología , Cirrosis Hepática Experimental/genética , Cirrosis Hepática Experimental/metabolismo , Cirrosis Hepática Experimental/patología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
Machine-learning methods can assist with the medical decision-making processes at the both the clinical and diagnostic levels. In this article, we first review historical milestones and specific applications of computer-based medical decision support tools in both veterinary and human medicine. Next, we take a mechanistic look at 3 archetypal learning algorithms-naive Bayes, decision trees, and neural network-commonly used to power these medical decision support tools. Last, we focus our discussion on the data sets used to train these algorithms and examine methods for validation, data representation, transformation, and feature selection. From this review, the reader should gain some appreciation for how these decision support tools have and can be used in medicine along with insight on their inner workings.
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Algoritmos , Toma de Decisiones Clínicas , Aprendizaje Automático , Medicina , Medicina Veterinaria , Animales , Teorema de Bayes , Árboles de Decisión , Humanos , Redes Neurales de la ComputaciónRESUMEN
The recently discovered interferon lambda 4 (IFN-λ4) is a new member of the human type III interferons which could induce a strong antiviral effect through the JAK-STAT cascade. However, hepatitis C virus (HCV) patients who are capable of expressing IFN-λ4 usually have poor response to IFN-α treatment, and the mechanism behind this paradox remains unknown. Here, we reported that IFN-λ4 desensitized IFN-α-stimulated JAK-STAT signalling. Microarray analysis revealed that IFN-λ4 could induce ubiquitin specific peptidase 18 (USP18), a known inhibitor of the type I IFN signalling pathway, in a more sustained pattern compared with type I interferon induction. Moreover, only HCV genotype 1b but not 2a replicon cells pretreated with IFN-λ4 had an attenuated response to type I IFN treatment, which might be due to the different level of USP18 expression. Consistently, knockdown of USP18 in HCV genotype 1b-containing replicon cells reversed the resistance induced by IFN-λ4 and promoted viral clearance. Finally, IFN-λ4 is also strongly associated with the poor response to IFN-α in a Chinese HCV genotype 1b cohort. In conclusion, these data indicate that IFN-λ4 attenuates the response of HCV genotype 1b to IFN-α therapy and inhibits the JAK-STAT signalling pathway by inducing USP18 expression.
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Endopeptidasas/metabolismo , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Interleucinas/metabolismo , Pueblo Asiatico , Hepacivirus/inmunología , Humanos , Transducción de Señal/efectos de los fármacos , Ubiquitina TiolesterasaRESUMEN
INTRODUCTION: Malignant ventricular arrhythmia (VA) and sudden cardiac death (SCD) have been reported in patients with mitral valve prolapse (MVP); however, effective risk stratification methods are still lacking. Myocardial fibrosis is thought to play an important role in the development of VA; however, observational studies have produced contradictory findings regarding the relationship between VA and late gadolinium enhancement (LGE) in MVP patients. The aim of this meta-analysis and systematic review of observational studies was to investigate the association between left ventricular LGE and VA in patients with MVP. METHODS: We searched the PubMed, Embase, and Web of Science databases from 1993 to 2023 to identify case-control, cross-sectional, and cohort studies that compared the incidence of VA in patients with MVP who had left ventricular LGE and those without left ventricular LGE. RESULTS: A total of 1464 subjects with MVP from 12 observational studies met the eligibility criteria. Among them, VA episodes were reported in 221 individuals (15.1%). Meta-analysis demonstrated that the presence of left ventricular LGE was significantly associated with an increased risk of VA (pooled risk ratio 2.96, 95% CI: 2.26-3.88, p for heterogeneity = 0.07, I2 = 40%). However, a meta-regression analysis of the prevalence of mitral regurgitation (MR) showed that the severity of MR did not significantly affect the association between the occurrence of LGE and VA (p = 0.079). CONCLUSION: The detection of LGE could be helpful for stratifying the risk of VA in patients with MVP.
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Medios de Contraste , Gadolinio , Imagen por Resonancia Cinemagnética , Prolapso de la Válvula Mitral , Humanos , Prolapso de la Válvula Mitral/complicaciones , Prolapso de la Válvula Mitral/diagnóstico , Prolapso de la Válvula Mitral/epidemiología , Prolapso de la Válvula Mitral/fisiopatología , Gadolinio/farmacología , Imagen por Resonancia Cinemagnética/métodos , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiología , Arritmias Cardíacas/epidemiología , Factores de Riesgo , Medición de Riesgo/métodosRESUMEN
Metabolic dysfunction-associated liver disease (MASLD) and steatohepatitis (MASH) are becoming the most common causes of chronic liver disease in the United States and worldwide due to the obesity and diabetes epidemics. It is estimated that by 2030 close to 100 million people might be affected and patients with type 2 diabetes are especially at high risk. Twenty to 30% of patients with MASLD can progress to MASH, which is characterized by steatosis, necroinflammation, hepatocyte ballooning, and in advanced cases, fibrosis progressing to cirrhosis. Clinically, it is recognized that disease progression in diabetic patients is accelerated and the role of various genetic and epigenetic factors, as well as cell-matrix interactions in fibrosis and stromal remodeling, have recently been recognized. While there has been great progress in drug development and clinical trials for MASLD/MASH, the complexity of these pathways highlights the need to improve diagnosis/early detection and develop more successful antifibrotic therapies that not only prevent but reverse fibrosis.
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Diabetes Mellitus Tipo 2 , Cirrosis Hepática , Humanos , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Progresión de la Enfermedad , Animales , Matriz Extracelular/metabolismo , Hígado Graso/metabolismo , Hígado Graso/etiologíaRESUMEN
CONTEXT: Extracting cancer symptom documentation allows clinicians to develop highly individualized symptom prediction algorithms to deliver symptom management care. Leveraging advanced language models to detect symptom data in clinical narratives can significantly enhance this process. OBJECTIVE: This study uses a pretrained large language model to detect and extract cancer symptoms in clinical notes. METHODS: We developed a pretrained language model to identify cancer symptoms in clinical notes based on a clinical corpus from the Enterprise Data Warehouse for Research at a healthcare system in the Midwestern United States. This study was conducted in 4 phases:1 pretraining a Bio-Clinical BERT model on one million unlabeled clinical documents,2 fine-tuning Symptom-BERT for detecting 13 cancer symptom groups within 1112 annotated clinical notes,3 generating 180 synthetic clinical notes using ChatGPT-4 for external validation, and4 comparing the internal and external performance of Symptom-BERT against a non-pretrained version and six other BERT implementations. RESULTS: The Symptom-BERT model effectively detected cancer symptoms in clinical notes. It achieved results with a micro-averaged F1-score of 0.933, an AUC of 0.929 internally, and 0.831 and 0.834 externally. Our analysis shows that physical symptoms, like Pruritus, are typically identified with higher performance than psychological symptoms, such as anxiety. CONCLUSION: This study underscores the transformative potential of specialized pretraining on domain-specific data in boosting the performance of language models for medical applications. The Symptom-BERT model's exceptional efficacy in detecting cancer symptoms heralds a groundbreaking stride in patient-centered AI technologies, offering a promising path to elevate symptom management and cultivate superior patient self-care outcomes.
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Registros Electrónicos de Salud , Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Procesamiento de Lenguaje Natural , AlgoritmosRESUMEN
Background and objective: Stress hyperglycemia is common in critically ill patients and is associated with poor prognosis. Whether this association exists in pulmonary hypertension (PH) patients is unknown. The present cohort study investigated the association of stress hyperglycemia with 90-day all-cause mortality in intensive care unit (ICU) patients with PH. Methods: Data of the study population were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. A new index, the ratio of admission glucose to HbA1c (GAR), was used to evaluate stress hyperglycemia. The study population was divided into groups according to GAR quartiles (Q1-Q4). The outcome of interest was all-cause mortality within 90 days, which was considered a short-term prognosis. Result: A total of 53,569 patients were screened. Ultimately, 414 PH patients were enrolled; 44.2% were male, and 23.2% were admitted to the cardiac ICU. As the GAR increased from Q2 to Q4, the groups had lower creatinine levels, longer ICU stays, and a higher proportion of renal disease. After adjusting for confounding factors such as demographics, vital signs, and comorbidities, an elevated GAR was associated with an increased risk of 90-day mortality. Conclusion: Stress hyperglycemia assessed by the GAR was associated with increased 90-day mortality in ICU patients with PH.
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Hiperglucemia , Hipertensión Pulmonar , Humanos , Masculino , Femenino , Estudios de Cohortes , Hipertensión Pulmonar/etiología , Enfermedad Crítica , Hiperglucemia/etiología , ComorbilidadRESUMEN
BACKGROUND: People with cancer frequently experience severe and distressing symptoms associated with cancer and its treatments. Predicting symptoms in patients with cancer continues to be a significant challenge for both clinicians and researchers. The rapid evolution of machine learning (ML) highlights the need for a current systematic review to improve cancer symptom prediction. OBJECTIVE: This systematic review aims to synthesize the literature that has used ML algorithms to predict the development of cancer symptoms and to identify the predictors of these symptoms. This is essential for integrating new developments and identifying gaps in existing literature. METHODS: We conducted this systematic review in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist. We conducted a systematic search of CINAHL, Embase, and PubMed for English records published from 1984 to August 11, 2023, using the following search terms: cancer, neoplasm, specific symptoms, neural networks, machine learning, specific algorithm names, and deep learning. All records that met the eligibility criteria were individually reviewed by 2 coauthors, and key findings were extracted and synthesized. We focused on studies using ML algorithms to predict cancer symptoms, excluding nonhuman research, technical reports, reviews, book chapters, conference proceedings, and inaccessible full texts. RESULTS: A total of 42 studies were included, the majority of which were published after 2017. Most studies were conducted in North America (18/42, 43%) and Asia (16/42, 38%). The sample sizes in most studies (27/42, 64%) typically ranged from 100 to 1000 participants. The most prevalent category of algorithms was supervised ML, accounting for 39 (93%) of the 42 studies. Each of the methods-deep learning, ensemble classifiers, and unsupervised ML-constituted 3 (3%) of the 42 studies. The ML algorithms with the best performance were logistic regression (9/42, 17%), random forest (7/42, 13%), artificial neural networks (5/42, 9%), and decision trees (5/42, 9%). The most commonly included primary cancer sites were the head and neck (9/42, 22%) and breast (8/42, 19%), with 17 (41%) of the 42 studies not specifying the site. The most frequently studied symptoms were xerostomia (9/42, 14%), depression (8/42, 13%), pain (8/42, 13%), and fatigue (6/42, 10%). The significant predictors were age, gender, treatment type, treatment number, cancer site, cancer stage, chemotherapy, radiotherapy, chronic diseases, comorbidities, physical factors, and psychological factors. CONCLUSIONS: This review outlines the algorithms used for predicting symptoms in individuals with cancer. Given the diversity of symptoms people with cancer experience, analytic approaches that can handle complex and nonlinear relationships are critical. This knowledge can pave the way for crafting algorithms tailored to a specific symptom. In addition, to improve prediction precision, future research should compare cutting-edge ML strategies such as deep learning and ensemble methods with traditional statistical models.
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PURPOSE: Identifying cancer symptoms in electronic health record (EHR) narratives is feasible with natural language processing (NLP). However, more efficient NLP systems are needed to detect various symptoms and distinguish observed symptoms from negated symptoms and medication-related side effects. We evaluated the accuracy of NLP in (1) detecting 14 symptom groups (ie, pain, fatigue, swelling, depressed mood, anxiety, nausea/vomiting, pruritus, headache, shortness of breath, constipation, numbness/tingling, decreased appetite, impaired memory, disturbed sleep) and (2) distinguishing observed symptoms in EHR narratives among patients with cancer. METHODS: We extracted 902,508 notes for 11,784 unique patients diagnosed with cancer and developed a gold standard corpus of 1,112 notes labeled for presence or absence of 14 symptom groups. We trained an embeddings-augmented NLP system integrating human and machine intelligence and conventional machine learning algorithms. NLP metrics were calculated on a gold standard corpus subset for testing. RESULTS: The interannotator agreement for labeling the gold standard corpus was excellent at 92%. The embeddings-augmented NLP model achieved the best performance (F1 score = 0.877). The highest NLP accuracy was observed in pruritus (F1 score = 0.937) while the lowest accuracy was in swelling (F1 score = 0.787). After classifying the entire data set with embeddings-augmented NLP, we found that 41% of the notes included symptom documentation. Pain was the most documented symptom (29% of all notes) while impaired memory was the least documented (0.7% of all notes). CONCLUSION: We illustrated the feasibility of detecting 14 symptom groups in EHR narratives and showed that an embeddings-augmented NLP system outperforms conventional machine learning algorithms in detecting symptom information and differentiating observed symptoms from negated symptoms and medication-related side effects.
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Registros Electrónicos de Salud , Procesamiento de Lenguaje Natural , Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/psicología , Femenino , Masculino , Algoritmos , Aprendizaje Automático , Narración , Persona de Mediana EdadRESUMEN
Plasma total homocysteine (tHcy) and kidney function are both associated with mortality risk, but the degree to which kidney function modifies the impact of tHcy on mortality remains unknown. This prospective cohort study included a total of 14,225 hypertensive adults. Cox proportional hazard regression was used to analyze the separate and combined association of tHcy and estimated glomerular filtration rate (eGFR) with all-cause and cause-specific mortality. Mediation analysis was conducted to explore the mediating effect of eGFR. During a median follow-up of 4.0 years, 805 deaths were identified, including 397 deaths from cardiovascular disease (CVD). There were significant, positive relationships of tHcy with all-cause mortality (per 5 µmol/L; HR: 1.09; 95% CI: 1.07, 1.11), CVD mortality (HR: 1.11; 95% CI: 1.08, 1.13), and non-CVD mortality (HR: 1.07; 95% CI: 1.04, 1.10). The proportions of eGFR mediating these relationships were 39.1%, 35.7%, and 49.7%, respectively. There were additive interactions between tHcy and eGFR. Compared with those with low tHcy (<15 µmol/L) and high eGFR (≥90 mL·min-1·1.73 m-2), participants with high tHcy (≥20 µmol/L) and low eGFR (<60 mL·min-1·1.73 m-2) had the highest risk of all-cause mortality (HR: 4.89; 95% CI: 3.81, 6.28), CVD mortality (HR: 5.80; 95% CI: 4.01, 8.40), and non-CVD mortality (HR: 4.25; 95% CI: 3.02, 5.97). In conclusion, among Chinese hypertensive adults, high tHcy and impaired kidney function were independently and jointly associated with higher risks of all-cause and cause-specific mortality. Importantly, kidney function explained most (nearly 40%) of the increased risk of mortality conferred by high tHcy.
Asunto(s)
Tasa de Filtración Glomerular , Homocisteína , Hipertensión , Humanos , Homocisteína/sangre , Masculino , Femenino , Persona de Mediana Edad , Hipertensión/mortalidad , Hipertensión/fisiopatología , Hipertensión/sangre , Estudios Prospectivos , Anciano , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/sangre , Adulto , Riñón/fisiopatología , Causas de Muerte , Análisis de MediaciónRESUMEN
Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, the pharmacological mechanism and target has not yet been fully elucidated. In this study, liver fibrosis was induced by CCl4 in wild-type mice and hepatocyte-specific extracellular matrix protein 1 (Ecm1)-deficient mice, which were separately treated with Sal B, ferrostatin-1, sorafenib or cilengitide. Erastin- or CCl4-induced hepatocyte ferroptosis models with or without Ecm1 gene knockdown were evaluated in vitro. Subsequently, the interaction between Ecm1 and xCT and the binding kinetics of Sal B and Ecm1 were determined. We found that Sal B significantly attenuated liver fibrosis in CCl4-induced mice. Ecm1 deletion in hepatocytes abolished the antifibrotic effect of Sal B. Mechanistically, Sal B protected against hepatocyte ferroptosis by upregulating Ecm1. Further research revealed that Ecm1 as a direct target for treating liver fibrosis with Sal B. Interestingly, Ecm1 interacted with xCT to regulate hepatocyte ferroptosis. Hepatocyte ferroptosis in vitro was significantly attenuated by Sal B treatment, which was abrogated after knockdown of Ecm1 in LO2 cells. Therefore, Sal B alleviates liver fibrosis in mice by targeting up-regulation of Ecm1 and inhibiting hepatocyte ferroptosis. The interaction between Ecm1 and xCT regulates hepatocyte ferroptosis.
Asunto(s)
Benzofuranos , Depsidos , Ferroptosis , Animales , Ratones , Transducción de Señal , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Hepatocitos/metabolismoRESUMEN
Atrial fibrillation (AF) patients are more susceptible to dementia, but the results about the effect of oral anticoagulants (OACs) on the risk of dementia are not consistent. We hypothesize that OAC is associated with a reduced risk of dementia with AF and that nonvitamin K antagonist oral anticoagulants (NOAC) are superior to vitamin K antagonists (VKA). Four databases were systematically searched until July 1, 2022. Two reviewers independently selected literature, evaluated quality, and extracted data. Data were examined using pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Fourteen research studies involving 910 patients were enrolled. The findings indicated that OACs were associated with a decreased risk of dementia (pooled HR: 0.68, 95% CI: 0.55-0.82, I2 = 87.7%), and NOACs had a stronger effect than VKAs (pooled HR: 0.87, 95% CI: 0.79-0.95, I2 = 72%), especially in participants with a CHA2DS2VASc score ≥ 2 (pooled HR: 0.85, 95% CI: 0.72-0.99). Subgroup analysis demonstrated no statistical significance among patients aged <65 years old (pooled HR: 0.83, 95% CI: 0.64-1.07), patients in "based on treatment" studies (pooled HR: 0.89, 95% CI: 0.75-1.06), or people with no stroke background (pooled HR: 0.90, 95% CI: 0.71-1.15). This analysis revealed that OACs were related to the reduction of dementia incidence in AF individuals, and NOACs were better than VKAs, remarkably in people with a CHA2DS2VASc score ≥ 2. The results should be confirmed by further prospective studies, particularly in patients in "based on treatment" studies aged <65 years old with a CHA2DS2VASc score < 2 or without a stroke background.