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Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two U.S. Food and Drug Administration-approved antifibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Objectives: Using an in silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. Methods: We investigated the antifibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: 1) in vitro in normal human lung fibroblasts; 2) in vivo in bleomycin and recombinant Ad-TGF-ß (adenovirus transforming growth factor-ß) murine models of pulmonary fibrosis; and 3) ex vivo in mice and human precision-cut lung slices from these two murine models as well as patients with IPF and healthy donors. Measurements and Main Results: In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-ß-stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial-mesenchymal transition, TGF-ß, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole-lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways, including epithelial-mesenchymal transition, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision-cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis. Conclusions: These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.
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Fibrose Pulmonar Idiopática , Inibidores de Proteínas Quinases , Animais , Humanos , Camundongos , Bleomicina/efeitos adversos , Fibroblastos/metabolismo , Fibrose , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinases da Família src/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
OBJECTIVE: Primary ciliary dyskinesia (PCD) is a heterogeneous disease characterized by the failure of mucociliary clearance. Dynein regulatory complex subunit 1 (DRC1) variants can cause PCD by disrupting the nexin link connecting the outer doublets. In this study, we aimed to investigate the clinical and functional impacts of DRC1 variants on respiratory cilia and sperm. METHODS: We identified and validated the DRC1 variant by using whole-exome and Sanger sequencing. High-speed video microscopy analysis (HSVA) was used to measure the nasal ciliary beating frequency and pattern in a patient and a healthy control. Hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) were applied to analyze the morphological and ultrastructural sperm defects resulting from the DRC1 variant. RESULTS: NM_145038.5:c.1296 G>A, p.(Trp432*), a novel homozygous DRC1 nonsense variant, was identified in a patient from a consanguineous Chinese family. The patient exhibited bronchiectasis, chronic sinusitis, situs solitus, and male infertility. The markedly reduced nasal nitric oxide production rate (3.0 nL/min) was consistent with PCD diagnosis. HSVA showed reduced bending capacity and higher beating frequency of nasal cilia in the patient compared with those in healthy control. The diagnosis of multiple morphological abnormalities of the sperm flagella (MMAF) was confirmed through sperm HE staining and TEM analysis. Following the intracytoplasmic sperm injection treatment, the patient fathered a healthy daughter. CONCLUSION: This report is the first to describe a novel DRC1 variant in a patient with PCD and MMAF, and in vitro fertilization was effective for treating infertility in this male patient. Our findings expand the genetic spectrum of PCD and MMAF, and provide a detailed clinical summary and functional analysis of patients with DRC1 variants.
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Transtornos da Motilidade Ciliar , Infertilidade Masculina , China , Transtornos da Motilidade Ciliar/genética , Humanos , Infertilidade Masculina/genética , Masculino , Proteínas Associadas aos Microtúbulos/genética , Mutação , Cauda do Espermatozoide , EspermatozoidesRESUMO
Genetics-associated asthenoteratozoospermia is often seen in patients with multiple morphological abnormalities of the sperm flagella (MMAF). Although 24 causative genes have been identified, these explain only approximately half of patients with MMAF. Since sperm flagella and motile cilia (especially respiratory cilia) have similar axonemal structures, many patients with MMAF also exhibit respiratory symptoms, such as recurrent airway infection, chronic sinusitis, and bronchiectasis, which are frequently associated with primary ciliary dyskinesia (PCD), another recessive disorder. Here, exome sequencing was conducted to evaluate the genetic cause in 53 patients with MMAF and classic PCD/PCD-like symptoms. Two homozygous missense variants and a compound-heterozygous variant in the BRWD1 gene were identified in three unrelated individuals. BRWD1 staining was detected in the whole flagella and respiratory cilia of normal controls but was absent in BRWD1-mutated individuals. Transmission electron microscopy and immunostaining demonstrated that BRWD1 deficiency in human affected respiratory cilia and sperm flagella differently, as the absence of outer and inner dynein arms in sperm flagellum and respiratory cilia, while with a decreased number and outer doublet microtubule defects of respiratory cilia. To our knowledge, this is the first report of a BRWD1-variant-related disease in humans, manifesting as an autosomal recessive form of MMAF and PCD/PCD-like symptoms. Our data provide a basis for further exploring the molecular mechanism of BRWD1 gene during spermatogenesis and ciliogenesis.
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Astenozoospermia/genética , Transtornos da Motilidade Ciliar/genética , Proteínas Nucleares/genética , Cauda do Espermatozoide/patologia , Espermatogênese/genética , Alelos , Humanos , Masculino , Análise do Sêmen , Sequenciamento do ExomaRESUMO
OBJECTIVE. The purpose of this study was to compare clinical and chest CT findings in patients with influenza A (H1N1) pneumonia and coronavirus disease (COVID-19) pneumonia. MATERIALS AND METHODS. Thirty patients with diagnosed influenza A (H1N1) virus infection (group A) and 30 patients with diagnosed COVID-19 (group B) were retrospectively enrolled in the present study. The clinical characteristics and chest CT findings of the two groups were compared. RESULTS. Fever, cough, expectoration, and dyspnea were the main symptoms in both groups with viral pneumonia, with cough and expectoration more frequently found in group A. Lymphopenia, an elevated C-reactive protein level, and an increased erythrocyte sedimentation rate were common laboratory test findings in the two groups. The median time from symptom onset to CT in group A and group B was 6 and 15 days, respectively, and the median total CT score of the pulmonary lobes involved was 6 and 13, respectively. Linear opacification, crazy-paving sign, vascular enlargement, were more common in group B. In contrast, bronchiectasis and pleural effusion were more common in group A. Other common CT features, including peripheral or peribronchovascular distribution, ground-glass opacities (GGOs), consolidation, subpleural line, air bronchogram, and bronchial distortion, did not show statistical significance. CONCLUSION. On CT, the significant differences between influenza A (H1N1) pneumonia and COVID-19 pneumonia were findings of linear opacification, crazy-paving sign, vascular enlargement, pleural thickening, and pleural effusion, which were more common in patients with COVID-19 pneumonia, and bronchiectasis and pleural effusion, which were more common in patients with influenza A (H1N1) pneumonia. Other imaging findings, including peripheral or peribronchovascular distribution, ground-glass opacities (GGO), consolidation, subpleural line, air bronchogram, and bronchial distortion, were not significantly different between the two patient groups.
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Betacoronavirus , Infecções por Coronavirus/diagnóstico por imagem , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Adulto , Idoso , COVID-19 , Infecções por Coronavirus/complicações , Feminino , Humanos , Influenza Humana/complicações , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Estudos Retrospectivos , SARS-CoV-2 , Avaliação de Sintomas , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Metagenomic next-generation sequencing (mNGS) has made a revolution in the mode of pathogen identification. We decided to explore the diagnostic value of blood and bronchoalveolar lavage fluid (BALF) as mNGS samples in pneumonia. METHODS: We retrospectively reviewed 467 mNGS results and assessed the diagnostic performance of paired blood and BALF mNGS in 39 patients with pneumonia. RESULTS: For bacteria and fungi, 16 patients had culture-confirmed pathogen diagnosis, while 13 patients were culture-negative. BALF mNGS was more sensitive than blood mNGS (81.3% vs. 25.0%, p=0.003), and the specificity in BALF and blood mNGS was not statistically significant different (76.9% vs. 84.6%, p=0.317). For 10 patients without culture test, treatments were changed in 2 patients. For viruses, Epstein-Barr virus was positive in blood mNGS in 9 patients. Human adenovirus was detected in both BALF and blood mNGS in 3 patients. CONCLUSION: Our study suggests that BALF mNGS is more sensitive than blood mNGS in detecting bacteria and fungi, but blood also has advantages to identify the pathogens of pneumonia, especially for some viruses.
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BACKGROUND: Atypical manifestations, such as elevated serum immunoglobulin-G4 (IgG4) and extra-pulmonary IgG4 positive plasmacyte infiltration, have been described in patients with eosinophilic granulomatosis with polyangiitis (EGPA), such complicated situation might not be readily differentiated from IgG4-related disease. CASE PRESENTATION: Here, we report an interesting and rare case of EGPA in a 41 year-old male with negative anti-neutrophil cytoplasmic antibodies (ANCAs), which showed abundant pulmonary IgG4-positive plasma cells infiltration and markedly elevated serum IgG4 levels without extra-pulmonary lesions of IgG4-related disease. The clinical characteristics hesitated us whether the diagnosis as EGPA overlapping with IgG4-related lung disease should be concluded because of the absence of storiform fibrosis and obliterative phlebitis with lymphoplasmacytic infiltration. The patient's systemic symptoms, pulmonary lesions, blood eosinophils count / percentage, and serum IgG4 levels were significantly improved with immunosuppressive therapy. CONCLUSIONS: We consider that the overlapping pathogenesis exists in the disease course of EGPA and IgG4-related disease, which may lead to interaction during the course of the diseases. And the utilization of diagnostic criteria for IgG4-related lung disease with the careful differentiation is needed in such cases.
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Doenças Autoimunes/complicações , Eosinófilos/patologia , Granulomatose com Poliangiite/complicações , Imunoglobulina G/sangue , Pulmão/patologia , Adulto , Diagnóstico Diferencial , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , Pulmão/diagnóstico por imagem , Masculino , Metilprednisolona/administração & dosagem , Sinusite/complicações , Tomografia Computadorizada por Raios XRESUMO
Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.
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Transtornos da Motilidade Ciliar , Sêmen , Humanos , Masculino , Animais , Camundongos , Sêmen/metabolismo , Dineínas/genética , Dineínas/metabolismo , Cílios/genética , Cílios/metabolismo , Mutação , Transtornos da Motilidade Ciliar/genéticaRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of sterol regulatory element binding protein (SREBP) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immunometabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in bronchoalveolar lavage (BAL) cells isolated from patients with IPF compared with healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti-miR-33 peptide nucleic acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. These studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a potentially novel therapeutic approach to treat this disease.
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Autofagia , Fibrose Pulmonar Idiopática , Macrófagos , MicroRNAs , Animais , Humanos , Camundongos , Autofagia/genética , Bleomicina/efeitos adversos , Homeostase , Fibrose Pulmonar Idiopática/metabolismo , Macrófagos/metabolismo , MicroRNAs/genética , Mitocôndrias/metabolismoRESUMO
INTRODUCTION: Chlamydia psittaci pneumonia has been a global public health hotspot in recent years. Although some scattered cases of C. psittaci pneumonia have been reported, there is a lack of large case studies worldwide. METHODS: In this multicenter, observational study, we recruited all consecutive patients with confirmed C. psittaci pneumonia from October 4, 2018, to October 23, 2020, in nine tertiary general hospitals in Central-South China. Epidemiologic and clinical data from patients' electronic medical records were collected and analyzed. RESULTS: One hundred and sixteen patients with C. psittaci pneumonia were included in the study. The mean age was 59.7 years. Fever (96.6%) and cough (65.5%) were the most common clinical symptoms. Most patients presented with an increase in the proportion of neutrophils, neutrophil to lymphocyte ratio, LDH, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and a significant decrease in lymphocytes. The main CT lung findings were consolidation (81%) and pleural effusion (35.3%), and bilateral lung consolidation was mainly found in severe patients. Chlamydia psittaci DNA was detected in BALF (bronchoalveolar lavage fluid) or blood samples by metagenomic next-generation sequencing (mNGS) in all patients. Use of quinolone was associated with shorter length of hospital stay and fever duration after antibiotic use. Multivariate logistic regression analysis indicated that respiratory support was associated with both severe pneumonia and in-hospital death. CONCLUSIONS: The clinical phenotype of C. psittaci pneumonia is complex and variable. mNGS is helpful in the diagnosis and treatment of C. psittaci pneumonia, and early treatment with quinolone may benefit patients.
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Primary ciliary dyskinesia (PCD) is a rare genetic disease caused by mutations of genes coding motile-cilia-related proteins. CCDC40 variants can cause PCD via disrupting the assembling of inner dynein and dynein regulating complex in cilia and flagella, but none has been reported associated with multiple morphological abnormalities of the sperm flagella (MMAF). We identified and validated the disease-causing variants in our patient via whole-exome and Sanger sequencing. We used high-speed video microscopy analysis (HSVA) and immunofluorescence to analyze the functional and structural deficiency of respiratory cilia. Papanicolaou staining and scanning electron microscope was applied to analyze the morphological sperm defects resulted from the PCD associated variants. We identified novel compound variants (c.901C>T, p.(Arg301*); c.2065_2068dup, p.(Ala690Glyfs*67)) in CCDC40 in a male patient with male infertility. HSVA revealed the rigid and stiff ciliary beating pattern. Immunofluorescence indicated loss of inner dynein arm protein DNAH2 both in cilia and the sperms of the patient. Diagnosis of MMAF was confirmed through sperm Papanicolaou staining and scanning electron microscope. We first describe a patient with a combination of PCD and MMAF associated with novel compound heterozygous variants in CCDC40. Our results present initial evidence that CCDC40 associated with MMAF, which expands the genetic spectrum of PCD and MMAF and provides precise clinical genetic counseling to this family.
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BACKGROUND: Legionella spp. has been well-recognized as an important cause of community-acquired pneumonia. Current community-acquired pneumonia guidelines recommended covering the treatment of Legionella because of the high mortality associated with inadequate antibiotic treatments. However, the symptom of Legionella pneumonia is non-specific, and routine diagnostic tests exhibit low sensitivity for Legionella spp., especially for non-Legionella pneumophila serogroup 1 strains. CASE PRESENTATION: We report a 53-year-old man without underlying diseases admitted to respiratory intensive care unit because of severe community-acquired pneumonia and respiratory failure. Although, the results of routine culture of bronchoalveolar lavage fluid and the Legionella urinary antigen test were all negative, metagenomic next-generation sequencing (mNGS) identified a great amount of DNA and RNA sequences of Legionella gormanii in bronchoalveolar lavage fluid while negative in blood sample. The presence of Legionella gormanii in bronchoalveolar lavage fluid was further confirmed by polymerase-chain-reaction and Sanger sequencing. CONCLUSION: Legionella gormanii has rarely been reported in patients with community-acquired pneumonia mainly due to lack of diagnostic test for non-Legionella pneumophila serogroup 1 strains. This is the first report of Legionella gormanii pneumonia in an immunocompetent patient detected by mNGS, which indicates that mNGS is a high-resolution and sensitive assay for the diagnosis and surveillance of Legionella infection.
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Objective: Whole-exome sequencing (WES) based copy number variation (CNV) analysis has been reported to improve the diagnostic rate in rare genetic diseases. In this study, we aim to find the disease-associated variants in a highly suspected primary ciliary dyskinesia (PCD) patient without a genetic diagnosis by routine WES analysis. Methods: We identified the CNVs using the "Exomedepth" package in an undiagnosed PCD patient with a negative result through routine WES analysis. RNA isolation, PCR amplification, and Sanger sequencing were used to confirm the variant. High-speed video microscopy analysis (HSVA) and immunofluorescence analysis were applied to detect the functional and structural deficiency of nasal cilia and sperm flagella. Papanicolaou staining was employed to characterize the morphology of sperm flagella. Results: NC_000002.11(NM_145038.5): g.26635488_26641606del, c.156-1724_244-2550del, r.156_243del, p. (Glu53Asnfs*13), a novel DRC1 homozygous CNV, was identified by WES-based CNV analysis rather than routine variants calling, in a patient from a non-consanguineous family. HSVA results showed no significant change in ciliary beating frequency but with reduced beating amplitude compared with normal control, and his spermatozoa were almost immotile. The diagnosis of multiple morphological abnormalities of the sperm flagella (MMAF) was established through sperm motility and morphology analysis. PCR amplification and Sanger sequencing confirmed the novel variant of DRC1. Immunofluorescence showed that both cilia and sperm flagella were deficient in protein expression related to the dynein regulatory complex. Conclusion: This report identifies a novel DRC1 disease-associated variant by WES-based CNV analysis from a highly suspected PCD patient with MMAF. Our findings not only expand the genetic spectrum of PCD with MMAF but suggest that in combination with CNV analysis might improve the efficiency of genetic tests.
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BACKGROUND: MicroRNAs are non-coding RNAs that negatively regulate gene networks. Previously, we reported that systemically delivered miR-29 mimic MRG-201 reduced fibrosis in animal models, supporting the consideration of miR-29-based therapies for idiopathic pulmonary fibrosis (IPF). METHODS: We generated MRG-229, a next-generation miR-29 mimic based on MRG-201 with improved chemical stability due to additional sugar modifications and conjugation with the internalization moiety BiPPB (PDGFbetaR-specific bicyclic peptide)1. We investigated the anti-fibrotic efficacy of MRG-229 on TGF-ß1 treated human lung fibroblasts (NHLFs), human precision cut lung slices (hPCLS), and in vivo bleomycin studies; toxicology was assessed in two animal models, rats, and non-human primates. Finally, we examined miR-29b levels in a cohort of 46 and 213 patients with IPF diagnosis recruited from Yale and Nottingham Universities (Profile Cohort), respectively. FINDINGS: The peptide-conjugated MRG-229 mimic decreased expression of pro-fibrotic genes and reduced collagen production in each model. In bleomycin-treated mice, the peptide-conjugated MRG-229 mimic downregulated profibrotic gene programs at doses more than ten-fold lower than the original compound. In rats and non-human primates, the peptide-conjugated MRG-229 mimic was well tolerated at clinically relevant doses with no adverse findings observed. In human peripheral blood from IPF patients decreased miR-29 concentrations were associated with increased mortality in two cohorts potentially identified as a target population for treatment. INTERPRETATION: Collectively, our results provide support for the development of the peptide-conjugated MRG-229 mimic as a potential therapy in humans with IPF. FUNDING: This work was supported by NIH NHLBI grants UH3HL123886, R01HL127349, R01HL141852, U01HL145567.
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Fibrose Pulmonar Idiopática , MicroRNAs , Humanos , Camundongos , Ratos , Animais , Pulmão/metabolismo , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/terapia , Bleomicina , MicroRNAs/genética , MicroRNAs/metabolismo , Fibroblastos/metabolismoRESUMO
BACKGROUND: Sepsis is a life-threatening multiple-organ dysfunction caused by dysregulation of host response to severe infection. Liver failure is a validated independent predictor of mortality. Accurate and rapid assessment of liver function is critical in patients with sepsis. However, an appropriate scoring system for liver function requires further development. OBJECTIVE: Our study aimed to validate the usefulness of the prothrombin time-international normalized ratio (PT-INR) to albumin ratio (PTAR) in predicting the mortality of patients with sepsis. METHODS: Data on a total of 4536 patients, obtained from the Multiparameter Intelligent Monitoring in Intensive Care III database, were included in our retrospective study. Logistic regression, Poisson regression with robust variance estimate analysis, and Cox proportional hazards models were used to explore the relationship between PTAR and mortality. Area under the curve (AUC) and decision curve analysis (DCA) were used to estimate the performance of PTAR in predicting the prognosis in septic patient. RESULTS: Multivariable Poisson regression showed that the relative risk (RR) of PTAR to ICU mortality, hospital mortality, and 28-day and 90-day mortality in septic patients was 1.26 (95% CI: 1.15-1.37), 1.24 (95% CI: 1.15-1.34), 1.23 (95% CI: 1.15-1.31), and 1.21 (95% CI: 1.13-1.28), respectively. Multivariable Cox regression showed that the hazard ratio (HR) of PTAR to 28-day mortality and 90-day mortality was 1.56 (95% CI: 1.44-1.70), and 1.55 (95% CI: 1.43-1.68), respectively. PTAR showed a moderate discrimination capacity in predicting hospital mortality (AUC: 0.655, 95% CI: 0.636-0.675) and 90-day mortality (AUC: 0.650, 95% CI: 0.633-0.667). CONCLUSION: The PTAR scoring system is a convenient tool for predicting the prognosis of patients with sepsis.
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OBJECTIVES: The impact of Pseudomonas aeruginosa on the prognosis of bronchiectasis remains controversial. This study aimed to explore the prognostic value of P. aeruginosa in adult patients with bronchiectasis in central-southern China. PATIENTS AND METHODS: This prospective cohort study enrolled 1,234 patients with bronchiectasis between 2013 and 2019. The independent impact of P. aeruginosa on all-cause mortality, annual exacerbations, and hospitalizations was assessed. RESULTS: P. aeruginosa was isolated from 244 patients (19.8%). A total of 188 patients died over a follow-up period of 16 (1-36) months. Patients with P. aeruginosa had a longer disease course, poorer lung function, more lung lobe involvement, and more severe Bronchiectasis Severity Index (BSI) stage than those without P. aeruginosa. The independent impact of P. aeruginosa was observed on frequent hospitalizations but not on mortality and frequent exacerbations. Moderate- or high-risk comorbidities increased the risk of mortality (hazard ratio [HR]: 1.93, 95% confidence interval [CI]: 1.26-2.95), and this effect was magnified by the presence of P. aeruginosa (HR: 2.11, 95% CI: 1.28-3.48). CONCLUSIONS: P. aeruginosa infection acts as a marker of disease severity as well as predictor of frequent hospitalizations. P. aeruginosa had no independent effect on all-cause mortality. P. aeruginosa combined with moderate- or high-risk comorbidities posed an increased risk of mortality. The management of comorbidities may be a critical target during the treatment of P. aeruginosa infection in bronchiectasis.KEY MESSAGE:P. aeruginosa increased the risk of frequent hospitalizations; however, it had no independent impact on all-cause mortality.P. aeruginosa combined with moderate- or high-risk comorbidities posed an increased risk of mortality.The management of comorbidities may be a critical target during the treatment of P. aeruginosa infection in bronchiectasis.
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Antibacterianos/uso terapêutico , Bronquiectasia/complicações , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/isolamento & purificação , Adulto , Bronquiectasia/mortalidade , China/epidemiologia , Comorbidade , Hospitalização/estatística & dados numéricos , Humanos , Prognóstico , Estudos Prospectivos , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/epidemiologia , Testes de Função Respiratória , Fatores de Risco , Índice de Gravidade de Doença , Taxa de SobrevidaRESUMO
BACKGROUND: Traboulsi syndrome is a rare disorder characterized by ectopia lentis and facial dysmorphism (large beaked nose), which was only reported in 18 individuals to date. It is caused by homozygous/compound heterozygous variants in the aspartate/asparagine-ß-hydroxylase (ASPH) gene, which hydroxylates the aspartic acid and asparagine in epidermal growth factor-like domains of various proteins. METHODS: Whole-exome and Sanger sequencing were used to identify the disease-causing gene of the patient in a consanguineous Chinese family. Domain analysis was applied to predict the impact of the variant on ASPH protein. RESULTS: Through exome and Sanger sequencing, we identified a novel homozygous ASPH variant (NM_004318.4:c.1910del/NP_004309.2: p.(Asn637MetfsTer15)) in the patient, which may lead to blockage of the ASPH function through truncating the AspH oxygenase domain of the ASPH protein and/or nonsense-mediated decay of the ASPH transcript. This is the first report of Traboulsi syndrome in a Chinese patient who was combined with ventricular septal defect, lung bullae, and recurrent spontaneous pneumothorax. CONCLUSION: Our results revealed the clinical characteristics of the first Chinese patient with Traboulsi syndrome. Additionally, our study expands the mutational spectrum of Traboulsi syndrome and provides information for clinical genetic counseling to this family.
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Proteínas de Ligação ao Cálcio/genética , Anormalidades Craniofaciais/genética , Ectopia do Cristalino/genética , Defeitos dos Septos Cardíacos/genética , Proteínas de Membrana/genética , Oxigenases de Função Mista/genética , Proteínas Musculares/genética , Pneumotórax/genética , Adulto , Proteínas de Ligação ao Cálcio/metabolismo , Anormalidades Craniofaciais/patologia , Ectopia do Cristalino/patologia , Mutação da Fase de Leitura , Defeitos dos Septos Cardíacos/patologia , Homozigoto , Humanos , Masculino , Proteínas de Membrana/metabolismo , Oxigenases de Função Mista/metabolismo , Proteínas Musculares/metabolismo , Degradação do RNAm Mediada por Códon sem Sentido , Linhagem , Fenótipo , Pneumotórax/patologia , Síndrome , Sequenciamento do ExomaRESUMO
The current pandemic of the coronavirus disease (COVID-19) has highlighted the importance of rapid control of the transmission of infectious diseases. This is particularly important for COVID-19, where many individuals are asymptomatic or have only mild symptoms but can still spread the disease. Current systems for controlling transmission rely on patients to report their symptoms to medical professionals and be able to recall and trace all their contacts from the previous few days. This is unrealistic in the modern world. However, existing smartphone-based GPS and social media technology may provide a suitable alternative. We, therefore, developed a mini-program within the app WeChat. This analyzes data from all users and traces close contacts of all patients. This permits early tracing and quarantine of potential sources of infection. Data from the mini-program can also be merged with other data to predict epidemic trends, calculate individual and population risks, and provide recommendations for individual and population protection action. It may also improve our understanding of how the disease spreads. However, there are a number of unresolved questions about the use of smartphone data for health surveillance, including how to protect individual privacy and provide safeguards against data breaches.
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Busca de Comunicante/métodos , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Vigilância em Saúde Pública/métodos , Inteligência Artificial , COVID-19 , Infecções por Coronavirus/transmissão , Sistemas de Informação Geográfica , Humanos , Aplicativos Móveis , Pneumonia Viral/transmissão , Privacidade , Quarentena , Smartphone , Mídias Sociais , Análise Espaço-TemporalRESUMO
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Genome-wide association studies in non-Asian population revealed a link between COPD and mutations in the PTCH1 gene encoding Patched1, a receptor in the Hedgehog signaling pathway important for lung morphogenesis and pulmonary function. The aim of this study was to investigate the association between PTCH1 polymorphisms and the COPD risk in the Chinese Han population. METHODS: We performed a case-control study including 296 patients with COPD and 300 healthy individuals. Single-nucleotide polymorphisms in the PTCH1 gene were identified and genotyped based on the linkage disequilibrium analysis in all participants. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression analysis after adjustment for age, gender, and smoking. RESULTS: In total, 28 single-nucleotide polymorphisms were identified in patients with COPD. Among them, "A" allele of rs28491365 (OR: 1.388, 95% CI: 1.055-1.827, Pâ=â0.018), and "G" alleles of rs10512248 (OR: 1.299, 95% CI: 1.021-1.653, Pâ=â0.033) and rs28705285 (OR: 1.359, 95% CI: 1.024-1.803, Pâ=â0.033; respectively) were significantly associated with an increased COPD risk. Genetic model analysis revealed that the "T/T" genotype of rs34695652 was associated with a decreased COPD risk under the recessive model (OR: 0.490, 95% CI: 0.270-0.880, Pâ=â0.010), whereas rs28504650/rs10512248 haplotype CG was significantly associated with an increased COPD risk after adjustment for age, gender, and smoking status (OR: 6.364, 95% CI: 1.220-33.292, Pâ=â0.028). CONCLUSIONS: The study provides a new insight into the role of PTCH1 polymorphisms in the susceptibility to COPD in the Chinese Han population.