Mechanism of intestinal microbiota disturbance promoting the occurrence and development of esophageal squamous cell carcinoma--based on microbiomics and metabolomics.

Esophageal squamous cell carcinoma (ESCC) is a high-risk malignant tumor that has been reported in China. Some studies indicate that gut microbiota disorders can affect the occurrence and development of ESCC, but the underlying mechanism remains unclear. In this study, we aimed to explore the possible underlying mechanisms using microbiomics and metabolomics. Fifty ESCC patients and fifty healthy controls were selected as the study subjects according to sex and age, and fecal samples were collected. 16S rDNA sequencing and LC‒MS were used for microbiomics and nontargeted metabolomics analyses. We found significant differences in the composition of the gut microbiota and metabolites between the ESCC patients and control individuals (P < 0.05). ESCC patients exhibited increased abundances of Fusobacteriaceae and Lactobacillus, increased levels of GibberellinA34 and decreased levels of 12-hydroxydodecanoic acid; these metabolites could be diagnostic and predictive markers of ESCC. An increase in the abundance of Enterobacteriaceae and Lactobacillus significantly reduced the content of L-aspartate and pantothenic acid, which may be involved in the occurrence and development of ESCC by downregulating the expression of proteins in the pantothenate and coenzyme A biosynthesis pathways. An imbalance in the intestinal flora may decrease the number of eosinophils in peripheral blood, resulting in the activation of an inflammatory response and immune dysfunction, leading to ESCC deterioration. We hypothesize that this imbalance in the gut microbiota can cause an imbalance in intestinal metabolites, which can activate carcinogenic metabolic pathways, affect inflammation and immune function, and play a role in the occurrence and development of ESCC.

Hospitalization, case fatality, comorbidities, and isolated pathogens of adult inpatients with pneumonia from 2013 to 2022: a real-world study in Guangzhou, China.

BACKGROUND: In the context of increasing population aging, ongoing drug-resistant pathogens and the COVID-19 epidemic, the changes in the epidemiological and clinical characteristics of patients with pneumonia remain unclear. This study aimed to assess the trends in hospitalization, case fatality, comorbidities, and isolated pathogens of pneumonia-related adult inpatients in Guangzhou during the last decade. METHODS: We retrospectively enrolled hospitalized adults who had doctor-diagnosed pneumonia in the First Affiliated Hospital of Guangzhou Medical University from January 1, 2013 to December 31, 2022. A natural language processing system was applied to automatically extract the clinical data from electronic health records. We evaluated the proportion of pneumonia-related hospitalizations in total hospitalizations, pneumonia-related in-hospital case fatality, comorbidities, and species of isolated pathogens during the last decade. Binary logistic regression analysis was used to assess predictors for patients with prolonged length of stay (LOS). RESULTS: A total of 38,870 cases were finally included in this study, with 70% males, median age of 64 (53, 73) years and median LOS of 7.9 (5.1, 12.8) days. Although the number of pneumonia-related hospitalizations showed an upward trend, the proportion of pneumonia-related hospitalizations decreased from 199.6 per 1000 inpatients in 2013 to 123.4 per 1000 in 2021, and the case fatality decreased from 50.2 per 1000 in 2013 to 23.9 per 1000 in 2022 (all P < 0.05). The most common comorbidities were chronic obstructive pulmonary disease, lung malignancy, cardiovascular diseases and diabetes. The most common pathogens were Pseudomonas aeruginosa, Candida albicans, Acinetobacter baumannii, Stenotrophomonas maltophilia, Klebsiella pneumoniae, and Staphylococcus aureus. Glucocorticoid use during hospitalization (Odd Ratio [OR] = 1.86, 95% Confidence Interval (CI): 1.14-3.06), immunosuppressant use during hospitalization (OR = 1.99, 1.14-3.46), ICU admission (OR = 16.23, 95%CI: 11.25-23.83), receiving mechanical ventilation (OR = 3.58, 95%CI: 2.60-4.97), presence of other underlying diseases (OR = 1.54, 95%CI: 1.15-2.06), and elevated procalcitonin (OR = 1.61, 95%CI: 1.19-2.19) were identified as independent predictors for prolonged LOS. CONCLUSION: The proportion of pneumonia-related hospitalizations and the in-hospital case fatality showed downward trends during the last decade. Pneumonia inpatients were often complicated by chronic underlying diseases and isolated with gram-negative bacteria. ICU admission was a significant predictor for prolonged LOS in pneumonia inpatients.

Comparison of extrafine beclomethasone dipropionate/formoterol fumarate dry powder inhaler and pressurized metered-dose inhaler in Chinese patients with asthma: the FORTUNE study.

OBJECTIVE: When selecting inhaled therapies, it is important to consider both the active molecules and the device. Extrafine formulation beclomethasone dipropionate plus formoterol fumarate (BDP/FF) has been available for some years delivered via pressurized metered-dose inhaler (pMDI). More recently, a breath-activated, multi-dose dry-powder inhaler (DPI), the NEXThaler, has been approved. The current study aimed to demonstrate the non-inferiority of BDP/FF delivered via the DPI vs. via the pMDI, in Chinese adults with asthma. METHODS: After a four-week run-in period, when all patients received BDP/FF pMDI 100/6 µg, two inhalations twice daily (BID), patients were randomized equally to BDP/FF pMDI or DPI, both 100/6 µg, two inhalations BID for 12 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF DPI vs. BDP/FF pMDI in terms of average pre-dose morning peak expiratory flow (PEF) over the entire treatment period. RESULTS: Of 252 and 242 patients in the DPI and pMDI groups, respectively, 88.5% and 88.8% completed the study. The primary objective was met, with no statistically significant difference between the treatments in average pre-dose morning PEF, and with the lower limit of the 95% CI above the -15 L/min non-inferiority margin (adjusted mean difference: 5.25 L/min [95% CI: -0.56, 11.06]). Adverse events were reported by 48.4% and 49.6% patients in the DPI and pMDI groups, respectively, most mild or moderate. CONCLUSIONS: The NEXThaler DPI is a similarly effective device to the pMDI for the administration of BDP/FF in adults, so extending the options available for the management of asthma.

Combining small airway parameters with conventional parameters obtained during spirometry to diagnose airflow obstruction: A cross-sectional study.

BACKGROUND AND OBJECTIVE: The use of small airway parameters generated by spirometry, namely forced expiratory flow between 25% and 75% of forced vital capacity (FVC) (FEF25%-75%) and forced expiratory flow at 50% and 75% of FVC (FEF50% and FEF75%, respectively), is widely discussed. We evaluated the importance of these spirometric parameters in a large Chinese population. METHODS: We conducted a cross-sectional observational study in which spirometry and bronchodilator responsiveness (BDR) data were collected in a healthcare centre from May 2021 to August 2022 and in a tertiary hospital from January 2017 to March 2022. Discordance was assessed between the classification of test results by the large airway parameters of forced expiratory volume in 1 second (FEV1) and FEV1/FVC ratio and by the small airway parameters of FEF25%-75%, FEF75% and FEF50%. The predictive power of Z-scores of spirometric parameters for airflow limitation and BDR was assessed using receiver operating characteristic curves. RESULTS: Our study included 26,658 people. Among people with a normal FVC (n = 14,688), 3.7%, 4.5% and 3.6% of cases exhibited normal FEV1/FVC ratio but impaired FEF25%-75%, FEF75% and FEF50%, respectively, while 6.8%-7.0% of people exhibited normal FEV1 but impaired FEF25%-75%, FEF75% and FEF50%. Using the Z-scores of combining both large and small airway parameters in spirometry showed the best area under the curve for predicting airflow limitation (0.90; 95% CI 0.87-0.94) and predicting BDR (0.72; 95% CI 0.71-0.73). CONCLUSION: It is important to consider both large and small airway parameters in spirometry to avoid missing a diagnosis of airflow obstruction.

Use of CAPTURE to Identify Individuals Who May or May Not Require Treatment for Chronic Obstructive Pulmonary Disease.

Rationale: The CAPTURE tool (Chronic Obstructive Pulmonary Disease [COPD] Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk) was developed to identify patients with undiagnosed COPD with an FEV1 <60% predicted or risk of exacerbation as treatment criteria. Objectives: To test the ability of CAPTURE to identify patients requiring treatment because of symptoms or risk of exacerbation or hospitalization. Methods: Data were from COMPASS (Clinical, Radiological and Biological Factors Associated with Disease Progression, Phenotypes and Endotypes of COPD in China), a prospective study of COPD, chronic bronchitis without airflow limitation (postbronchodilator FEV1/FVC ratio ≥0.70), and healthy never-smokers. CAPTURE was tested as questions alone and with peak expiratory flow measurement. Sensitivity, specificity, and positive and negative predicted values (PPV and NPV) were calculated for COPD Assessment Test (CAT) scores ⩾10 versus <10, modified Medical Research Council (mMRC) scores ⩾2 versus <2, and at least one moderate exacerbation or hospitalization in the previous year versus none. Measurements and Main Results: Patients with COPD (n = 1,696) had a mean age of 65 ± 7.5 years, and 90% were male, with a postbronchodilator FEV1 of 66.5 ± 20.1% predicted. Control participants (n = 307) had a mean age of 60.2 ± 7.0 years, and 65% were male, with an FEV1/FVC ratio of 0.78 ± 0.04. CAPTURE using peak expiratory flow showed the best combination of sensitivity and specificity. Sensitivity and specificity were 68.5% and 64.0%, respectively, to detect a CAT score ⩾10; 85.6% and 61.0% to detect an mMRC score ⩾2; 63.5% and 55.6% to detect at least one moderate exacerbation; and 70.2% and 59.4% to detect at least one hospitalization. PPVs ranged from 15.6% (moderate exacerbations) to 47.8% (CAT score). NPVs ranged from 80.8% (CAT score) to 95.6% (mMRC score). Conclusions: CAPTURE has good sensitivity to identify patients with COPD who may require treatment because of increased symptoms or risk of exacerbations or hospitalization, including those with an FEV1 >60% predicted. High NPV values show that CAPTURE can also exclude those who may not require treatment. Clinical trial registered with www.clinicaltrials.gov (NCT04853225).

Supervised training models with or without manual lesion delineation outperform clinicians in distinguishing pulmonary cryptococcosis from lung adenocarcinoma on chest CT.

BACKGROUND: The role of artificial intelligence (AI) in the discrimination between pulmonary cryptococcosis (PC) and lung adenocarcinoma (LA) warrants further research. OBJECTIVES: To compare the performances of AI models with clinicians in distinguishing PC from LA on chest CT. METHODS: Patients diagnosed with confirmed PC or LA were retrospectively recruited from three tertiary hospitals in Guangzhou. A deep learning framework was employed to develop two models: an undelineated supervised training (UST) model utilising original CT images, and a delineated supervised training (DST) model utilising CT images with manual lesion annotations provided by physicians. A subset of 20 cases was randomly selected from the entire dataset and reviewed by clinicians through a network questionnaire. The sensitivity, specificity and accuracy of the models and the clinicians were calculated. RESULTS: A total of 395 PC cases and 249 LA cases were included in the final analysis. The internal validation results for the UST model showed a sensitivity of 85.3%, specificity of 81.0%, accuracy of 83.6% and an area under the curve (AUC) of 0.93. Similarly, the DST model exhibited a sensitivity of 88.2%, specificity of 88.1%, accuracy of 88.2% and an AUC of 0.94. The external validation of the two models yielded AUC values of 0.74 and 0.77, respectively. The average sensitivity, specificity and accuracy of 102 clinicians were determined to be 63.1%, 53.7% and 59.3%, respectively. CONCLUSIONS: Both models outperformed the clinicians in distinguishing between PC and LA on chest CT, with the UST model exhibiting comparable performance to the DST model.

Comprehensive appraisal of lung function in young COPD patients: a single center observational study.

PURPOSE: The present study aimed to investigate the clinical characteristics and lung function impairment in young people diagnosed with chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: We retrospectively enrolled patients with COPD who underwent symptom assessment and comprehensive pulmonary function tests at the First Affiliated Hospital of Guangzhou Medical University between August 2017 and March 2022. The patients were categorized into two groups based on age: a young COPD group (aged 20-50 years) and an old COPD group (aged > 50 years). RESULTS: A total of 1282 patients with COPD were included in the study, with 76 young COPD patients and 1206 old COPD patients. Young COPD patients exhibited a higher likelihood of being asymptomatic, lower rates of smoking, and a lower smoking index compared to old COPD patients. Although young COPD patients had higher median post-bronchodilator forced expiratory volume in 1 s (post-BD FEV1) (1.4 vs.1.2 L, P = 0.019), diffusing capacity of the lung for carbon monoxide (DLCO) (7.2 vs. 4.6, P<0.001), and a lower median residual volume to total lung capacity ratio (RV/TLC) compared to their older counterparts, there were no differences observed in severity distribution by GOLD categories or the proportion of lung hyperinflation (RV/TLC%pred > 120%) between two groups. Surprisingly, the prevalence of reduced DLCO was found to be 71.1% in young COPD, although lower than in old COPD (85.2%). CONCLUSION: Young COPD showed fewer respiratory symptoms, yet displayed a similar severity distribution by GOLD categories. Furthermore, a majority of them demonstrated lung hyperinflation and reduced DLCO. These results underscore the importance of a comprehensive assessment of lung function in young COPD patients.

Association between mixed metal exposure and stroke risk in Shanxi Province: a case-control study.

BACKGROUND: Stroke is the second leading cause of death for all human beings and poses a serious threat to human health. Environmental exposure to a mixture of metals may be associated with the occurrence and development of stroke, but the evidence in the Chinese population is not yet conclusive. OBJECTIVES: This study evaluated the association between stroke risk and 13 metals METHODS: Metal concentrations in whole blood samples from 100 stroke cases and 100 controls were measured by ICP-MS. The cumulative impact of mixed metal on stroke risk was investigated by using three statistical models, BKMR, WQS and QGC. RESULTS: The case group had higher concentrations of Mg, Mn, Zn, Se, Sn, and Pb than the control group (p<0.05). BKMR model indicated a correlation between the risk of stroke and exposure to mixed metals. WQS model showed that Mg (27.2 %), Se (25.1 %) and Sn (14.8 %) were positively correlated with stroke risk (OR=1.53; 95 %Cl: 1.03-2.37, p=0.013). The QGC model showed that Mg (49.2 %) was positively correlated with stroke risk, while Ti (31.7 %) was negatively correlated with stroke risk. CONCLUSIONS: Mg may be the largest contributor to the cumulative effect of mixed metal exposure on stroke risk, and the interaction between metals requires more attention. These findings could provide scientific basis for effectively preventing stroke by managing metals in the environment.

Association of respiratory symptoms and lung function with occupation in the multinational Burden of Obstructive Lung Disease (BOLD) study.

BACKGROUND: Chronic obstructive pulmonary disease has been associated with exposures in the workplace. We aimed to assess the association of respiratory symptoms and lung function with occupation in the Burden of Obstructive Lung Disease study. METHODS: We analysed cross-sectional data from 28 823 adults (≥40 years) in 34 countries. We considered 11 occupations and grouped them by likelihood of exposure to organic dusts, inorganic dusts and fumes. The association of chronic cough, chronic phlegm, wheeze, dyspnoea, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)/FVC with occupation was assessed, per study site, using multivariable regression. These estimates were then meta-analysed. Sensitivity analyses explored differences between sexes and gross national income. RESULTS: Overall, working in settings with potentially high exposure to dusts or fumes was associated with respiratory symptoms but not lung function differences. The most common occupation was farming. Compared to people not working in any of the 11 considered occupations, those who were farmers for ≥20 years were more likely to have chronic cough (OR 1.52, 95% CI 1.19-1.94), wheeze (OR 1.37, 95% CI 1.16-1.63) and dyspnoea (OR 1.83, 95% CI 1.53-2.20), but not lower FVC (ß=0.02 L, 95% CI -0.02-0.06 L) or lower FEV1/FVC (ß=0.04%, 95% CI -0.49-0.58%). Some findings differed by sex and gross national income. CONCLUSION: At a population level, the occupational exposures considered in this study do not appear to be major determinants of differences in lung function, although they are associated with more respiratory symptoms. Because not all work settings were included in this study, respiratory surveillance should still be encouraged among high-risk dusty and fume job workers, especially in low- and middle-income countries.

Global, regional, and national burden of asthma and its attributable risk factors from 1990 to 2019: a systematic analysis for the Global Burden of Disease Study 2019.

BACKGROUND: The burden of asthma in terms of premature death or reduced quality of life remains a huge issue. It is of great importance to evaluate asthma burden geographically and time trends from 1990 to 2019 and to assess the contributions of age, period, and cohort effects at global level. METHODS: Asthma prevalence, deaths, and disability adjusted life years (DALYs) as well as risk-attributable burden were collected from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 database and were compared by age and sex. The Smoothing Splines models were used to estimate the relationship between asthma DALYs and the sociodemographic index (SDI). The Age-Period-Cohort model was used to determine effects of ages, periods, and birth cohorts on disease rates. RESULTS: Between 1990 and 2019, the declines were 24.05% (95% uncertainty interval [UI] - 27.24 to - 20.82) in age-standardized asthma prevalence, 51.3% (- 59.08 to - 43.71) in mortality, and 42.55% (- 48.48 to - 36.61) in DALYs rate. However, the burden of asthma continued to rise, with an estimated 262.41 million prevalent cases globally (95% UI 224.05 to 309.45). Asthma caused greater DALYs in females than in males among people aged 20 years and older. The lowest age-standardized DALYs rate was observed at a SDI of approximately 0.70. The Longitudinal age curves showed an approximate W-shaped pattern for asthma prevalence and a likely J-shaped pattern for asthma mortality. The period effect on prevalence and mortality of asthma decreased from 1990 to 2019. Compared with the 1955-1959 birth cohort, the prevalence relative risk (RR) of asthma was highest in the 1905-1909 birth cohort, whereas the mortality RR continued to decline. At the global level, the percentages of high body-mass index, occupational asthmagens, and smoking contributing to DALYs due to asthma were 16.94%, 8.82%, and 9.87%, respectively. CONCLUSIONS: Although the age-standardized rates of asthma burden declined in the past 30 years, the overall burden of asthma remains severe. High body mass index becomes the most important risk factor for DALYs due to asthma at the global level.

Effects of Lianhuaqingwen Capsules in adults with mild-to-moderate coronavirus disease 2019: an international, multicenter, double-blind, randomized controlled trial.

BACKGROUND: In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However, the lack of blinding and limited sample sizes decreased the level of clinical evidence. OBJECTIVES: To evaluate the efficacy and safety of LHQW capsule in adults with mild-to-moderate COVID-19. METHODS: We conducted a double-blind randomized controlled trial in adults with mild-to-moderate COVID-19 (17 sites from China, Thailand, Philippine and Vietnam). Patients received standard-of-care alone or plus LHQW capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the median time to sustained clinical improvement or resolution of nine major symptoms. RESULTS: The full-analysis set consisted of 410 patients in LHQW capsules and 405 in placebo group. LHQW significantly shortened the primary endpoint in the full-analysis set (4.0 vs. 6.7 days, hazards ratio: 1.63, 95% confidence interval: 1.39-1.90). LHQW capsules shortened the median time to sustained clinical improvement or resolution of stuffy or runny nose (2.8 vs. 3.7 days), sore throat (2.0 vs. 2.6 days), cough (3.2 vs. 4.9 days), feeling hot or feverish (1.0 vs. 1.3 days), low energy or tiredness (1.3 vs. 1.9 days), and myalgia (1.5 vs. 2.0 days). The duration to sustained clinical improvement or resolution of shortness of breath, headache, and chills or shivering did not differ significantly between the two groups. Safety was comparable between the two groups. No serious adverse events were reported. INTERPRETATION: LHQW capsules promote recovery of mild-to-moderate COVID-19 via accelerating symptom resolution and were well tolerated. Trial registration ChiCTR2200056727 .

Organic extracts in PM2.5 are the major triggers to induce ferroptosis in SH-SY5Y cells.

As a major air pollutant, PM2.5 can induce apoptosis of nerve cells, causing impairment of the learning and memory capabilities of humans and animals. Ferroptosis is a newly discovered way of programmed cell death. It is unclear whether the neurotoxicity induced by PM2.5 is related to the ferroptosis of nerve cells. In this study, we observed the changes in ferroptosis hallmarks of SH-SY5Y cells after exposure to various doses (40, 80, and 160 µg/mL PM2.5) for 24 h, exposure to 40 µg/mL PM2.5 for various times (24, 48, and 72 h), as well as exposure to various components (Po, organic extracts; Pw, water-soluble extracts; Pc, carbon core component). The results showed that PM2.5 reduced the cell viability, the content of GSH, and the activity of GSH-PX and SOD in SH-SY5Y cells with exposure dose and duration increasing. On the other hand, PM2.5 increased the content of iron, MDA, and the level of lipid ROS in SH-SY5Y cells with exposure dose and duration increasing. Additionally, PM2.5 reduced the expression levels of HO-1, NRF2, SLC7A11, and GPX4. The ferroptosis inhibitors Fer-1 and DFO significantly increase the cells viabilities and significantly reversed the changes of other above ferroptosis hallmarks. We also observed the different effects on ferroptosis hallmarks in the SH-SY5Y cells exposed to PM2.5 (160 µg/mL) and its various components (organic extracts, water-soluble extracts, and carbon core) for 24 h. We found that only the organic extracts shared similar results with PM2.5 (160 µg/mL). This study demonstrated that PM2.5 induced ferroptosis of SH-SY5Y cells, and organic extracts might be the primary component that caused ferroptosis.

Association between NAD+ levels and anaemia among women in community-based study.

Nicotinamide adenine dinucleotide (NAD+ ) level is the protective factor of cardiovascular diseases (CVDs). In addition, anaemia is a risk factor of adverse cardiovascular outcomes in women. However, there are limited data about the association between NAD+ and anaemia. The aim of this study was to evaluate association of NAD+ with anaemia among women. A total of 727 females from Jidong community were included in the current analysis. NAD+ levels were tested by the cycling assay and HPLC assay using whole blood samples. Anaemia was determined by haemoglobin (Hb) concentration, and the subtypes of anaemia were further defined according to mean corpuscular volume (MCV) in blood. Multivariable logistic analysis was used to analyse the association between NAD+ levels and anaemia or its subtypes. The mean age of recruited subjects was 42.7 years. The proportion of anaemia by NAD+ levels quartiles were 19.7% (35/178), 4.8% (9/189), 3.4% (6/178) and 2.7% (5/182). Haematological parameters including haemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC) and red blood count (RBC) increased over NAD+ quartiles. Red cell volume distribution width (RDW) decreased over NAD+ quartiles. Compared with the lowest quartile of NAD+ levels (<27.6µM), the adjusted odds ratios with 95% confidence intervals of the top quartile were 0.15 (0.06-0.41) for anaemia, 0.05 (0.01-0.36) for microcytic anaemia and 0.37 (0.10-1.36) for normocytic anaemia respectively. Higher NAD+ levels were significantly associated with lower prevalence of anaemia among women, especially microcytic anaemia and normocytic anaemia. Haematological parameters might serve as a predictor of the blood NAD+ levels.

MUC5B regulates goblet cell differentiation and reduces inflammation in a murine COPD model.

BACKGROUND: Airway mucus hypersecretion is one of the important pathological features of chronic obstructive pulmonary disease (COPD). MUC5B is the main mucin expressed in the airways of COPD patients and has been indicated to play an important role in airway defense. However, the specific biological function of MUC5B in COPD and the possible mechanism are not clear. METHODS: We established a COPD model with 24-week-old MUC5B-/- mice exposed to cigarette smoke and tested our hypothesis through lung function tests, HE and PAS staining, immunohistochemistry (IHC), western blot, q-PCR and ELISA. RESULTS: Compared with MUC5B+/+ mice, MUC5B-/- mice had worse general condition and lung function, increased inflammatory infiltration, reduced goblet cell differentiation as indicated by decreased PAS staining (PAS grade: 1.8 ± 0.24 vs. 0.6 ± 0.16), reduced MUC5AC expression (ELISA: 0.30 ± 0.01 vs. 0.17 ± 0.01 mg/ml, q-PCR: 9.4 ± 1.7 vs. 4.1 ± 0.1 fold, IHC score: 3.1 ± 0.9 vs. 1.6 ± 0.7), increased macrophage secretion of inflammatory factors (TNF-α and IL-6) and expression of downstream pathway factors (ERK1/2 and NF-κB), decreased expression of SPDEF and STAT6, and increased expression of FOXA2. CONCLUSION: The protective effect of MUC5B in the development of COPD was mediated by the promotion of goblet cell differentiation and the inhibition of inflammation. The role of MUC5B in regulating inflammation was related to macrophage function, and goblet cell differentiation was promoted by the induced expression of STAT6 and SPDEF. This study describes a mechanism of mucus hypersecretion and identifies MUC5B as a new target for the treatment of mucus hypersecretion.

Deep learning for spirometry quality assurance with spirometric indices and curves.

BACKGROUND: Spirometry quality assurance is a challenging task across levels of healthcare tiers, especially in primary care. Deep learning may serve as a support tool for enhancing spirometry quality. We aimed to develop a high accuracy and sensitive deep learning-based model aiming at assisting high-quality spirometry assurance. METHODS: Spirometry PDF files retrieved from one hospital between October 2017 and October 2020 were labeled according to ATS/ERS 2019 criteria and divided into training and internal test sets. Additional files from three hospitals were used for external testing. A deep learning-based model was constructed and assessed to determine acceptability, usability, and quality rating for FEV1 and FVC. System warning messages and patient instructions were also generated for general practitioners (GPs). RESULTS: A total of 16,502 files were labeled. Of these, 4592 curves were assigned to the internal test set, the remaining constituted the training set. In the internal test set, the model generated 95.1%, 92.4%, and 94.3% accuracy for FEV1 acceptability, usability, and rating. The accuracy for FVC acceptability, usability, and rating were 93.6%, 94.3%, and 92.2%. With the assistance of the model, the performance of GPs in terms of monthly percentages of good quality (A, B, or C grades) tests for FEV1 and FVC was higher by ~ 21% and ~ 36%, respectively. CONCLUSION: The proposed model assisted GPs in spirometry quality assurance, resulting in enhancing the performance of GPs in quality control of spirometry.

A ratiometric fluorescent nanoprobe for signal amplification monitoring of intracellular telomerase activity.

Telomerase is considered a valuable diagnostic and prognostic cancer biomarker. Accurate and reliable detection of telomerase activity is of great value in clinical diagnosis, screening of inhibitors, and therapeutics. Here, we developed a novel amplified fluorescence resonance energy transfer (FRET) nanoprobe for highly sensitive and reliable monitoring of intracellular telomerase activity. The nanoprobe (QDSA@DNA) was composed of a streptavidin-modified quantum dot (QDSA) which was functionalized with a telomerase primer sequence (TP) and Cy5-tagged signal switching sequence (SS) through biotin-streptavidin interaction. When the nanoprobe was assembled, the Cy5 was in close proximity to the QDSA, resulting in high FRET efficiency from the QDSA to Cy5. In the presence of telomerase, the TP could be extended to produce telomeric repeat units, which was complementary to the loop of SS. Thus, the SS could hybridize with elongated sequences to form a rigid double-stranded structure, which forced the Cy5 away from the surface of the QDSA, causing low FRET efficiency. Furthermore, due to the production of multiple repeat units by telomerase, multiple hairpin structures could be opened, yielding significant fluorescence ratio (FQDsa/FCy5) enhancement for sensing of telomerase activity. In this way, the combination of a FRET and target-assisted strategy in a nanoprobe improved the detection accuracy and amplified the detection signal, respectively. The QDSA@DNA nanoprobe also showed high selectivity, excellent nuclease stability, and good biocompatibility. More importantly, this nanoprobe was found to be an excellent platform for efficient monitoring of intracellular telomerase activity, providing a potential platform in tumor diagnosis and screening of telomerase-related inhibitors.

Deep Learning for Automatic Upper Airway Obstruction Detection by Analysis of Flow-Volume Curve.

BACKGROUND: Due to the similar symptoms of upper airway obstruction to asthma, misdiagnosis is common. Spirometry is a cost-effective screening test for upper airway obstruction and its characteristic patterns involving fixed, variable intrathoracic and extrathoracic lesions. We aimed to develop a deep learning model to detect upper airway obstruction patterns and compared its performance with that of lung function clinicians. METHODS: Spirometry records were reviewed to detect the possible condition of airway stenosis. Then they were confirmed by the gold standard (e.g., computed tomography, endoscopy, or clinic diagnosis of upper airway obstruction). Images and indices derived from flow-volume curves were used for training and testing the model. Clinicians determined cases using spirometry records from the test set. The deep learning model evaluated the same data. RESULTS: Of 45,831 patients' spirometry records, 564 subjects with curves suggesting upper airway obstruction, after verified by the gold standard, 351 patients were confirmed. These cases and another 200 cases without airway stenosis were used as the training and testing sets. 432 clinicians evaluated 20 cases of each of the three patterns and 20 no airway stenosis cases (n = 80). They assigned an accuracy of 41.2% (±15.4) (interquartile range: 27.5-52.5%), with poor agreements (κ = 0.12). For the same cases, the model generated a correct detection of 81.3% (p < 0.0001). CONCLUSIONS: Deep learning could detect upper airway obstruction patterns from other classic patterns of ventilatory defects with high accuracy, whereas clinicians presented marked errors and variabilities. The model may serve as a support tool to enhance clinicians' correct diagnosis of upper airway obstruction using spirometry.

Prevalence and Population-Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study.

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objectives: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV1-to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.

Technical performance analysis of different types of spirometers.

BACKGROUND: The spirometer is an important element in lung function examinations, and its accuracy is directly related to the accuracy of the results of these examinations and to the diagnosis and treatment of diseases. Our aim was to conduct a performance analysis of the detection techniques of differential pressure and ultrasonic portable spirometers commonly used in China. METHODS: A standard flow/volume simulator was used to analyze the performance (accuracy, repeatability, linearity, impedance, and so on) of portable spirometers, 4 imported and 6 domestic, based on 13 curves generated by different air sources in the ISO 26782:2009 standard. A Bland-Altman diagram was used to evaluate the consistency between the values measured by the spirometers and the simulator. RESULTS: The pass rates for accuracy, repeatability, linearity, and impedance for the 10 different portable spirometers were 50%, 100%, 70%, and 70%, respectively. Only 30% (3/10) of the spirometers-2 domestic and 1 imported-met all standards of quality and performance evaluation, while the rest were partially up to standard. In the consistency evaluation, only 3 spirometers were within both the consistency standard range and the acceptability range. CONCLUSION: The quality and performance of different types of portable spirometers commonly used in the clinic differ. The use of a standard flow/volume simulator is helpful for the standard evaluation of the technical performance of spirometers.

Quality inspection and result analysis of the spirometer calibration cylinder.

BACKGROUND: To understand the accuracy of volume calibration syringes used in China and compare the difference between new and old volume calibration syringes, technical testing was performed on volume calibration syringes in clinical lung function instruments. MATERIALS AND METHODS: A standard validator device (Model 1180, Hans Rudolph, USA) was used to perform leak testing and volume accuracy testing for calibration syringes. Sixteen volume calibration syringes from 8 brands (CareFusion in Germany, Vyaire in Germany, Yaeger in Germany, Vitalograph in the United Kingdom, MGC Diagnostics in the United States, U-Breath in Zhejiang, China, Wendi in Ningbo, Zhejiang, and Boya in Ningbo, China) were tested. RESULTS: A total of 75% (12/16) of the volume calibration syringes passed the pressure decay leak test, 69% (11/16) of the volume calibration syringes passed the volume accuracy and repeatability test, and 56% (9/16) passed both tests; there was no significant difference in the total passing of the new and old volume calibration syringe quality tests (P > 0.05). CONCLUSIONS: A standard validator device should be used for both leakage tests and volume accuracy and repeatability tests to ensure the reliability of volume calibration syringes. It is suggested that the quality verification of volume calibration syringes should be regularly conducted to ensure the accuracy of the pulmonary function tests.