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OBJECTIVES: While chest radiograph (CXR) is the first-line imaging investigation in patients with respiratory symptoms, differentiating COVID-19 from other respiratory infections on CXR remains challenging. We developed and validated an AI system for COVID-19 detection on presenting CXR. METHODS: A deep learning model (RadGenX), trained on 168,850 CXRs, was validated on a large international test set of presenting CXRs of symptomatic patients from 9 study sites (US, Italy, and Hong Kong SAR) and 2 public datasets from the US and Europe. Performance was measured by area under the receiver operator characteristic curve (AUC). Bootstrapped simulations were performed to assess performance across a range of potential COVID-19 disease prevalence values (3.33 to 33.3%). Comparison against international radiologists was performed on an independent test set of 852 cases. RESULTS: RadGenX achieved an AUC of 0.89 on 4-fold cross-validation and an AUC of 0.79 (95%CI 0.78-0.80) on an independent test cohort of 5,894 patients. Delong's test showed statistical differences in model performance across patients from different regions (p < 0.01), disease severity (p < 0.001), gender (p < 0.001), and age (p = 0.03). Prevalence simulations showed the negative predictive value increases from 86.1% at 33.3% prevalence, to greater than 98.5% at any prevalence below 4.5%. Compared with radiologists, McNemar's test showed the model has higher sensitivity (p < 0.001) but lower specificity (p < 0.001). CONCLUSION: An AI model that predicts COVID-19 infection on CXR in symptomatic patients was validated on a large international cohort providing valuable context on testing and performance expectations for AI systems that perform COVID-19 prediction on CXR. KEY POINTS: ⢠An AI model developed using CXRs to detect COVID-19 was validated in a large multi-center cohort of 5,894 patients from 9 prospectively recruited sites and 2 public datasets. ⢠Differences in AI model performance were seen across region, disease severity, gender, and age. ⢠Prevalence simulations on the international test set demonstrate the model's NPV is greater than 98.5% at any prevalence below 4.5%.
Assuntos
COVID-19 , Aprendizado Profundo , Humanos , Inteligência Artificial , Radiografia Torácica/métodos , Tomografia Computadorizada por Raios X/métodos , Estudos RetrospectivosRESUMO
Mitochondrial dysfunction has been reported in chronic obstructive pulmonary disease (COPD). Transfer of mitochondria from mesenchymal stem cells to airway smooth muscle cells (ASMCs) can attenuate oxidative stress-induced mitochondrial damage. It is not known whether mitochondrial transfer can occur between structural cells in the lungs or what role this may have in modulating bioenergetics and cellular function in healthy and COPD airways. Here, we show that ASMCs from both healthy ex-smokers and subjects with COPD can exchange mitochondria, a process that happens, at least partly, via extracellular vesicles. Exposure to cigarette smoke induces mitochondrial dysfunction and leads to an increase in the donation of mitochondria by ASMCs, suggesting that the latter may be a stress response mechanism. Healthy ex-smoker ASMCs that receive mitochondria show increases in mitochondrial biogenesis and respiration and a reduction in cell proliferation, irrespective of whether the mitochondria are transferred from healthy ex-smoker or COPD ASMCs. Our data indicate that mitochondrial transfer between structural cells is a homeostatic mechanism for the regulation of bioenergetics and cellular function within the airways and may represent an endogenous mechanism for reversing the functional consequences of mitochondrial dysfunction in diseases such as COPD.
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Doença Pulmonar Obstrutiva Crônica , Metabolismo Energético , Humanos , Pulmão/metabolismo , Mitocôndrias/metabolismo , Músculo Liso , Doença Pulmonar Obstrutiva Crônica/metabolismoRESUMO
BACKGROUND: Patients with chronic asthma have thicker intrapulmonary airways measured on high resolution computed tomography (HRCT). We determined whether the presence of lower airway bacteria was associated with increased airway wall thickness. METHODS: In 56 patients with stable severe asthma, sputum specimens obtained either spontaneously or after induction with hypertonic saline were cultured for bacteria and thoracic HRCT scans obtained. Wall thickness (WT) and area (WA) expressed as a ratio of airway diameter (D) and total area, respectively, were measured at five levels. RESULTS: Positive bacterial cultures were obtained in 29 patients, with H. influenzae, P. aeruginosa and S. aureus being the commonest strains. Logistic regression analysis showed that this was associated with the duration of asthma and the exacerbations during the past year. In airways > 2 mm, there was no significant difference in WA (67.5 ± 5.4 vs 66.4 ± 5.4) and WT/D (21.6 ± 2.7 vs 21.3 ± 2.4) between the culture negative versus positive groups. Similarly, in airways (≤ 2 mm), there were no significant differences in these parameters. The ratio of âwall area to Pi was negatively correlated with FEV1% predicted (p < 0.05). CONCLUSIONS: Bacterial colonization of the lower airways is common in patients with chronic severe asthma and is linked to the duration of asthma and having had exacerbations in the past year, but not with an increase in airway wall thickness.
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Remodelação das Vias Aéreas , Asma/microbiologia , Haemophilus influenzae/isolamento & purificação , Pseudomonas aeruginosa/isolamento & purificação , Índice de Gravidade de Doença , Escarro/microbiologia , Staphylococcus aureus/isolamento & purificação , Adulto , Idoso , Asma/diagnóstico por imagem , Feminino , Volume Expiratório Forçado , Humanos , Modelos Logísticos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Tomografia Computadorizada por Raios X/métodosRESUMO
PURPOSE OF REVIEW: The purpose of this review article is to provide an up-to-date summary on the current evidence for or against the use of lung function tests as screening and diagnostic tools for airflow obstruction in chronic obstructive pulmonary disease (COPD), and to consider the relevant issues in context. RECENT FINDINGS: COPD is characterized by chronic respiratory symptoms and airflow limitation with only partial reversibility on lung function testing. However, screening on a population basis or of an enriched 'at-risk' subset like chronic smokers is not supported by findings from previous epidemiological studies, screening trials or in currently published clinical management guidelines by professional societies and review bodies. The definition of airflow obstruction and the classification of disease severity of COPD also differ slightly between guidelines and statements from different professional societies. SUMMARY: Given the experience from previous screening trials and controversial classification of airflow obstruction by severity, it is impossible to have accurate screening results for COPD based on lung function tests alone. Clinical respiratory symptoms should be taken into consideration in terms of the diagnosis and management of COPD, as well as in any screening trial or programme that is to be attempted or implemented.
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Programas de Rastreamento/métodos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fumar/efeitos adversos , Fatores Etários , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Guias de Prática Clínica como Assunto , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Testes de Função Respiratória , Índice de Gravidade de Doença , Fumar/epidemiologia , Fumar/fisiopatologia , Capacidade VitalRESUMO
Hydrogen sulfide (H(2)S) is synthesized intracellularly by the enzymes cystathionine-γ-lyase and cystathionine-ß-synthase (CBS), and is proposed to be a gasotransmitter with effects in modulating inflammation and cellular proliferation. We determined a role of H(2)S in airway smooth muscle (ASM) function. ASM were removed from resection or transplant donor lungs and were placed in culture. Proliferation of ASM was induced by FCS and the proinflammatory cytokine, IL-1ß. Proliferation of ASM and IL-8 release were measured by bromodeoxyuridine incorporation and ELISA, respectively. Exposure of ASM to H(2)S "donors" inhibited this proliferation and IL-8 release. Methemoglobin, a scavenger of endogenous H(2)S, increased DNA synthesis induced by FCS and IL-1ß. In addition, methemoglobin increased IL-8 release induced by FCS, but not by IL-1ß, indicating a role for endogenous H(2)S in these systems. Inhibition of CBS, but not cystathionine-γ-lyase, reversed the inhibitory effect of H(2)S on proliferation and IL-8 release, indicating that this is dependent on CBS. CBS mRNA and protein expression were inhibited by H(2)S donors, and were increased by methemoglobin, indicating that CBS is the main enzyme responsible for endogenous H(2)S production. Finally, we found that exogenous H(2)S inhibited the phosphorylation of extracellular signal-regulated kinase-1/2 and p38, which could represent a mechanism by which H(2)S inhibited cellular proliferation and IL-8 release. In summary, H(2)S production provides a novel mechanism for regulation of ASM proliferation and IL-8 release. Therefore, regulation of H(2)S may represent a novel approach to controlling ASM proliferation and cytokine release that is found in patients with asthma.
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Brônquios/metabolismo , Proliferação de Células , Sulfeto de Hidrogênio/metabolismo , Interleucina-8/metabolismo , Miócitos de Músculo Liso/metabolismo , Brônquios/efeitos dos fármacos , Brônquios/imunologia , Brônquios/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/antagonistas & inibidores , Cistationina gama-Liase/metabolismo , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Humanos , Interleucina-1beta/metabolismo , Metemoglobina/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Morfolinas/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/patologia , Compostos Organotiofosforados/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Soro/metabolismo , Sulfetos/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain-a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain. We highlight gaps in understanding of the mechanisms of acute and chronic COVID-19-associated cough and post-COVID syndrome, consider potential ways to reduce the effect of COVID-19 by controlling cough, and suggest future directions for research and clinical practice. Although neuromodulators such as gabapentin or opioids might be considered for acute and chronic COVID-19 cough, we discuss the possible mechanisms of COVID-19-associated cough and the promise of new anti-inflammatories or neuromodulators that might successfully target both the cough of COVID-19 and the post-COVID syndrome.
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COVID-19/complicações , COVID-19/fisiopatologia , Tosse/etiologia , Inflamação/etiologia , Doenças do Sistema Nervoso/etiologia , Neuroimunomodulação , Tosse/fisiopatologia , Humanos , Inflamação/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , SARS-CoV-2 , SíndromeRESUMO
BACKGROUND: Studies have demonstrated that higher rates of antibiotic resistance are found in countries with higher antibiotic consumption. The global increase in antibiotic consumption is a major public health concern. OBJECTIVES: The objective of this study was to describe the antibiotic dispensing patterns in public hospitals in Hong Kong from 2000 to 2015. METHODS: We acquired data on all hospital admissions with any antibiotics dispensed from 2000 to 2015 from the Hong Kong public hospitals. The annual proportion of hospital admissions with antibiotics dispensed was estimated and stratified by age group. An interrupted time series analysis was conducted to examine any potential change in tetracycline dispensing after the release of the new clinical practice guideline. RESULTS: A total of 35,535,506 antibiotic prescriptions were dispensed among 2,161,360 unique hospitalized patients from 2000 to 2015. Antibiotics were dispensed in 29.2% of all hospital admissions in the public hospitals, the annual proportions of hospital admissions with antibiotics dispensed increased over the study period from 27.87% in 2000 to 31.39% in 2015, ranging from 27.17 to 31.39%. However, a significant increase was only observed in age groups of 5-19, 20-44, and 85 years or above when stratifying by age. In the interrupted time series analysis, a change in trend was detected for tetracycline dispensing that coincided with the time of publication of the new clinical practice guideline. CONCLUSIONS: We found that the overall volume of antibiotic use increased between 2000 and 2015. The rise in the dispensing of carbapenems in our study is concerning. The significant change in tetracycline use after being recommended as one of the preferred regimens demonstrated that the change in the clinical practice guideline had an immediate effect on the antibiotic prescribing practice in Hong Kong public hospitals.
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Antibacterianos/administração & dosagem , Padrões de Prática Médica/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Hong Kong , Hospitalização , Hospitais Públicos , Humanos , Lactente , Pacientes Internados , Análise de Séries Temporais Interrompida , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: The relationship between OSA and glucose metabolism remains controversial. This retrospective study investigated the relationship between OSA and incident type 2 diabetes (T2D) in a clinic cohort of Chinese adults in Hong Kong, and the effect of long-term CPAP treatment. METHODS: Data for diagnosis of incident T2D and CPAP usage were obtained from the territory-wide electronic health administration system and records of protocolized evaluation of CPAP adherence at the sleep clinic. The relationship between baseline OSA and incident T2D and the effect of CPAP therapy were examined by Cox regression models. Risk of incident T2D over the continuum of apnea-hypopnea index was examined with cubic spline analysis. RESULTS: Of 1,206 subjects with overnight sleep studies and clinical assessment in 2006 through 2013, 152 developed diabetes (median follow-up, 7.3 years). In fully adjusted models, untreated moderate or patients with severe OSA had higher risk of developing diabetes, hazard ratios 2.01 (95% CI, 1.06-3.81) and 2.62 (95% CI, 1.40-4.93) respectively, with a trend to plateau in those with severe OSA. No interaction was demonstrated between OSA and obesity. Regular CPAP use, which was attained in about one-third of subjects with moderate-severe OSA, was associated with reduction of diabetes incidence from 3.41 to 1.61 per 100 person-years, and of adjusted hazard risk to that of non-OSA. CONCLUSIONS: OSA severity independently predicted incident diabetes. Regular long-term CPAP use was associated with reduced risk of incident T2D, after adjustment for various baseline metabolic risk factors and subsequent body weight change.
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Pressão Positiva Contínua nas Vias Aéreas , Diabetes Mellitus Tipo 2/complicações , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/terapia , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVES: We aimed to describe patterns in the usage of antivirals to treat influenza virus infection in hospitals in Hong Kong from 2000 through 2015. METHODS: We analyzed centralized electronic health records that included dispensation information and diagnosis codes. Information collected on admissions included patient age, sex, admission year and month, and medications dispensed, and were matched with the first 15 discharge diagnosis codes. We divided monthly admission episodes by relevant population denominators to obtain admission rates, and stratified analyses by drug type, age group, and diagnosis codes. RESULTS: Amantadine was used for influenza treatment in the early 2000s but changed with recommendations to avoid its use in 2006, and is now mainly used to treat Parkinson's disease. Oseltamivir usage increased substantially in 2009 and is now commonly used, with almost 40,000 hospitalizations treated with oseltamivir in the years 2012 through 2015, 66% of which was in persons ≥65 years of age. During the entire study period, of the 98,253 admission episodes in which oseltamivir was dispensed, 40,698 (41%) included a diagnosis code for influenza, and 80,283 (82%) included any diagnosis code for respiratory illness. CONCLUSIONS: The amount of oseltamivir used from 2012-15 was comparable to a separate ecological estimate of around 13,000 influenza-associated hospitalizations per year on average. We did not have access to individual patient laboratory testing data.
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Antivirais/uso terapêutico , Revisão de Uso de Medicamentos , Influenza Humana/tratamento farmacológico , Idoso , Feminino , História do Século XXI , Hong Kong , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
UNLABELLED: We confirmed the performance of an array method for plasma epidermal growth factor receptor (EGFR) mutation detection and showed the association of plasma EGFR mutation with survival outcomes. BACKGROUND: Noninvasive detection of epidermal growth factor receptor (EGFR) mutation in plasma is feasible and could be adjunct for therapeutic monitoring especially when repeated biopsy of tumor tissue is challenging. The aims of this study were to establish the diagnostic performance of peptide nucleic acid-locked nucleic acid polymerase chain reaction followed by custom array for plasma EGFR mutation and to evaluate the association of detection with clinical characteristics and survival outcomes. MATERIALS AND METHODS: Plasma genomic DNA from consecutive advanced lung cancer subjects was tested for EGFR mutations before anticancer treatment, and compared with mutation status in tumor tissue. Clinical characteristics were compared between patients who were EGFR-mutant and wild type; and within EGFR mutants, whether EGFR mutations could be detected in plasma. RESULTS: In 74 lung cancer patients, the sensitivity, specificity, and positive and negative predictive values of plasma EGFR detection were 79.1%, 96.8%, 97.1%, and 76.9%, respectively. EGFR mutants with concomitant detection of plasma EGFR mutation showed worse survival compared with mutants with no concomitant plasma mutation detected in biopsy specimens. CONCLUSION: Plasma EGFR mutation detected using this method demonstrated high diagnostic performance. In EGFR mutants, plasma EGFR mutation detection correlated not only EGFR mutation status in biopsy but was also associated with worse prognosis compared with EGFR mutant without plasma EGFR mutation detection.
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Adenocarcinoma/diagnóstico , Receptores ErbB/genética , Neoplasias Pulmonares/diagnóstico , Mutação/genética , Adenocarcinoma/mortalidade , Idoso , Análise Mutacional de DNA/métodos , Receptores ErbB/sangue , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e Especificidade , Análise de SobrevidaRESUMO
Indacaterol is a novel once-daily long-acting ß2-agonist (LABA) for the treatment of chronic obstructive pulmonary disease (COPD) that is currently completing Phase II and Phase III trials. It represents the first of a group of drugs now referred to as the 'ultra-LABAs'. It has recently gained approval in Europe, and is pending regulatory review in the USA. Indacaterol produces a rapid and sustained bronchodilation that lasts for at least 24 h in patients with COPD. To date, 1-year studies with indacaterol indicate that it can be taken once daily with good overall safety and tolerability profiles. The therapeutic potential for indacaterol is supported by data on patient-reported outcomes with an improvement in symptoms such as dyspnea, exercise capacity and quality of life, and a reduction in exacerbations. It is likely that indacaterol could be used in conjunction with other agents such as inhaled corticosteroids and anticholinergics for the treatment of COPD as a single once-daily combination treatment.