Characterization of bronchoalveolar lavage fluid microbiota in acute exacerbations of bronchiectasis with non-tuberculous mycobacterial detection.

OBJECTIVES: Non-tuberculous mycobacteria (NTM) frequently colonize the airways of patients with bronchiectasis; however, there has been limited research into airway microbiota composition and predisposing factors for NTM detection during acute bronchiectasis exacerbations. METHODS: This study enrolled 34 patients with bronchiectasis experiencing acute exacerbations. Metagenomic next-generation sequencing was used to detect microbiota in bronchoalveolar lavage fluid (BALF), and bioinformatics methods were used for the comparative analysis of meaningful microbiota in the BALF of patients with acute exacerbations of bronchiectasis. A correlation analysis was conducted to identify susceptibility factors for NTM in patients with bronchiectasis. RESULTS: Compared with patients with community-acquired pneumonia, patients with bronchiectasis had higher detection rates of NTM (38.2%), Pseudomonas aeruginosa, and Haemophilus influenzae. Patients with NTM-positive bronchiectasis had lower body mass index and lipid profiles than patients who were NTM-negative. Metagenomic next-generation sequencing of BALF revealed patients who were NTM-positive had increased relative abundance of Rothia and other anaerobic genera compared with patients who were NTM-negative. Patients who were NTM-positive also showed higher levels of Streptococcus parasanguinis at the species level. Elevated Rothia mucilaginosa and S. parasanguinis correlated with decreased percentages of clusters of differentiation 3+ T lymphocytes and clusters of differentiation 3+ T-cell subgroups in peripheral blood. CONCLUSIONS: NTM colonization increases the risk of acute bronchiectasis exacerbations. Low body mass index, lipid levels, and isolation of R. mucilaginosa and S. parasanguinis in BALF are susceptibility factors for NTM colonization in patients with bronchiectasis.

Genetic Insights into the Gut-Lung Axis: Mendelian Randomization Analysis on Gut Microbiota, Lung Function, and COPD.

Background: Chronic obstructive pulmonary disease (COPD) is a respiratory disorder with a complex etiology involving genetic and environmental factors. The dysbiosis of gut microbiota has been implicated in COPD. Mendelian Randomization (MR) provides a tool to investigate causal links using genetic variants as instrumental variables. This study aims to employ MR analysis to explore the causal relationship between gut microbiota, lung function, and COPD. Methods: We utilized genome-wide association study (GWAS) data from MiBioGen, UK Biobank and FinnGen, which were related to gut microbial taxa, lung function parameters including forced vital capacity in one second (FEV1), forced vital capacity (FVC), and percentage of predicted FEV1 (FEV1%pred), as well as GWAS data for COPD. MR analysis was conducted to assess the causal effects of gut microbiota on lung function and the risk of COPD. Sensitivity analysis was utilized to examine the stability of the causal relationships. Multiple testing and reverse analysis were employed to evaluate the robustness of these relationships. Results: Using the IVW method, 64 causal correlations were identified. Through conducting sensitivity analysis, multiple testing, and reverse analysis, we identified 14 robust and stable causal relationships. The bacterial taxa that showed a positive association with lung function included Desulfovibrionaceae, Erysipelotrichales, Desulfovibrionales, Clostridiales, Clostridia, Deltaproteobacteria and Erysipelotrichia, while Selenomonadales and Negativicutes showed a negative association with lung function. The abundance of Holdemanella were positively correlated with the risk of COPD, while FamilyXIII exhibited a negative correlation with the risk of COPD. Conclusion: Several microbial taxa were discovered to have a positive causal correlation with lung function, offering potential insights into the development of probiotics. The presence of microbial taxa negatively correlated with lung function and positively correlated with COPD emphasized the potential impact of gut microbiota dysbiosis on respiratory health.

A phase 4 multicentre, 2×2 factorial randomised, double-blind, placebo-controlled trial to investigate the efficacy and safety of tobramycin inhalation solution for Pseudomonas aeruginosa eradication in bronchiectasis: ERASE.

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.

Promyelocytic leukemia zinc finger controls type 2 immune responses in the lungs by regulating lineage commitment and the function of innate and adaptive immune cells.

Type 2 immune responses are critical for host defense, mediate allergy and Th2-high asthma. The transcription factor, promyelocytic leukemia zinc finger (PLZF), has emerged as a significant regulator of type 2 inflammation in the lung; however, its exact mechanism remains unclear. In this review, we summarized recent findings regarding the ability of PLZF to control the development and function of innate lymphoid cells (ILCs), iNKT cells, memory T cells, basophils, and other immune cells that drive type 2 responses. We discussed the important role of PLZF in the pathogenesis of Th2-high asthma. Collectively, prior studies have revealed the critical role of PLZF in the regulation of innate and adaptive immune cells involved in type 2 inflammation in the lung. Therefore, targeting PLZF signaling represents a promising therapeutic approach to suppress Th2-high asthma.

Anti-inflammatory roles of type I interferon signaling in the lung.

Excessive or persistent inflammation may have detrimental effects on lung structure and function. Currently, our understanding of conserved host mechanisms that control the inflammatory response remains incompletely understood. In this study, we investigated the role of type I interferon signaling in the inflammatory response against diverse clinically relevant stimuli. Using mice deficient in type I interferon signaling (IFNAR1-/-), we demonstrate that the absence of interferon signaling resulted in a robust and persistent inflammatory response against Pseudomonas aeruginosa, lipopolysaccharide, and chemotherapeutic agent bleomycin. The elevated inflammatory response in IFNAR1-/- mice was manifested as elevated myeloid cells, such as macrophages and neutrophils, in the bronchoalveolar lavage. The inflammatory cell response in the IFNAR1-/- mice persisted to 14 days and there is impaired recovery and fibrotic remodeling of the lung in IFNAR1-/- mice after bleomycin injury. In the Pseudomonas infection model, the elevated inflammatory cell response led to improved bacterial clearance in IFNAR1-/- mice, although there was similar lung injury and survival. We performed RNA sequencing of lung tissue in wild-type and IFNAR1-/- mice after LPS and bleomycin injury. Our unbiased analysis identified differentially expressed genes between IFNAR1-/- and wild-type mice, including previously unknown regulation of nucleotide-binding oligomerization domain (NOD)-like receptor signaling, retinoic acid-inducible gene-I (RIG-I) signaling, and necroptosis pathway by type I interferon signaling in both models. These data provide novel insights into the conserved anti-inflammatory mechanisms of the type I interferon signaling.NEW & NOTEWORTHY Type I interferons are known for their antiviral activities. In this study, we demonstrate a conserved anti-inflammatory role of type I interferon signaling against diverse stimuli in the lung. We show that exacerbated inflammatory response in the absence of type I interferon signaling has both acute and chronic consequences in the lung including structural changes.

Shufeng Jiedu capsule for acute exacerbation of chronic obstructive pulmonary disease: a protocol of multicentre, randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) represents one of the leading causes of death worldwide. Published clinical trials suggest that the Chinese patent herbal medicine Shufeng Jiedu capsule (SFJD) is safe and may be effective for treating acute exacerbations of COPD (AECOPD). However, these effects have been reported with low or very low certainty evidence. This trial aims to evaluate the effectiveness and safety of SFJD for AECOPD. METHODS AND ANALYSIS: This study is designed as a multicentre, randomised, double-blind, placebo-controlled trial. Three hundred patients with moderate or severe hospitalised AECOPD will be recruited in Beijing, Shanghai and Hefei. Participants will be randomly assigned to SFJD and usual care or placebo and usual care at a ratio of 1:1. SFJD and placebo will be administered orally four capsules three times daily for 7 consecutive days followed by an 8-week follow-up period. The primary outcome will be COPD symptom severity as measured by the EXAcerbation of Chronic Pulmonary Disease Tool score. Secondary outcomes include clinical symptoms, quality of life, length of hospital stay, a total dose of antibiotics, the frequency of recurrence of AECOPD, haematological biomarkers, death and adverse events. This study will answer the question of whether SFJD was safe to use and will improve symptoms in people with AECOPD, and will therefore reduce the necessity for antibiotics, the risk and duration of admission to hospital, and the risk of recurrence. ETHICS AND DISSEMINATION: The ethics committee of the first affiliated hospital of Anhui Medical University, Beijing University of Chinese Medicine affiliated Dongzhimen hospital and fifth people's hospital of Shanghai Fudan University approved the study protocol. Informed written consent will be obtained from all the participants. The results of this trial will be disseminated at academic conferences and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN99049821.

CRISPR-based diagnostics of different biomolecules from nucleic acids, proteins, and small molecules to exosomes.

CRISPR-based detection technologies have been widely explored for molecular diagnostics. However, the challenge lies in converting the signal of different biomolecules, such as nucleic acids, proteins, small molecules, exosomes, and ions, into a CRISPR-based nucleic acid detection signal. Understanding the detection of different biomolecules using CRISPR technology can aid in the development of practical and promising detection approaches. Unfortunately, existing reviews rarely provide an overview of CRISPR-based molecular diagnostics from the perspective of different biomolecules. Herein, we first introduce the principles and characteristics of various CRISPR nucleases for molecular diagnostics. Then, we focus on summarizing and evaluating the latest advancements in CRISPR-based detection of different biomolecules. Through a comparison of different methods of amplification and signal readout, we discuss how general detection methods can be integrated with CRISPR. Finally, we conclude by identifying opportunities for the improvement of CRISPR in quantitative, amplification-free, multiplex, all-in-one, and point-of-care testing (POCT) purposes.

Effect of hydrogen/oxygen therapy for ordinary COVID-19 patients: a propensity-score matched case-control study.

BACKGROUND: Hydrogen/oxygen therapy contribute to ameliorate dyspnea and disease progression in patients with respiratory diseases. Therefore, we hypothesized that hydrogen/oxygen therapy for ordinary coronavirus disease 2019 (COVID-19) patients might reduce the length of hospitalization and increase hospital discharge rates. METHODS: This retrospective, propensity-score matched (PSM) case-control study included 180 patients hospitalized with COVID-19 from 3 centers. After assigned in 1:2 ratios by PSM, 33 patients received hydrogen/oxygen therapy and 55 patients received oxygen therapy included in this study. Primary endpoint was the length of hospitalization. Secondary endpoints were hospital discharge rates and oxygen saturation (SpO2). Vital signs and respiratory symptoms were also observed. RESULTS: Findings confirmed a significantly lower median length of hospitalization (HR = 1.91; 95% CIs, 1.25-2.92; p < 0.05) in the hydrogen/oxygen group (12 days; 95% CI, 9-15) versus the oxygen group (13 days; 95% CI, 11-20). The higher hospital discharge rates were observed in the hydrogen/oxygen group at 21 days (93.9% vs. 74.5%; p < 0.05) and 28 days (97.0% vs. 85.5%; p < 0.05) compared with the oxygen group, except for 14 days (69.7% vs. 56.4%). After 5-day therapy, patients in hydrogen/oxygen group exhibited a higher level of SpO2 compared with that in the oxygen group (98.5%±0.56% vs. 97.8%±1.0%; p < 0.001). In subgroup analysis of patients received hydrogen/oxygen, patients aged < 55 years (p = 0.028) and without comorbidities (p = 0.002) exhibited a shorter hospitalization (median 10 days). CONCLUSION: This study indicated that hydrogen/oxygen might be a useful therapeutic medical gas to enhance SpO2 and shorten length of hospitalization in patients with ordinary COVID-19. Younger patients or those without comorbidities are likely to benefit more from hydrogen/oxygen therapy.

Systems pharmacology approach to explore the mechanisms of shufeng Jiedu Capsule on treating H1N1 infection.

BACKGROUND: Influenza caused by the H1N1 virus still affects human health. There is currently no effective strategy against H1N1 virus infection. The present study is to evaluate the mechanism of Shufeng Jiedu Capsule (SFJDC) in the treatment of H1N1 infection using an integrated systems pharmacology approach and experimental validation. SFJDC is recommended for the treatment of H1N1 infection in traditional Chinese medicine (TCM), whose mechanism of action is not precise. METHODS: We systematically analyzed SFJDC using a systematic pharmacology and ADME screening model, and predicted effective targets using systematic drug targeting (SysDT) algorithm. Subsequently, the network of interactions between compounds and targets was built to help in the discovery of new drugs. In addition, the pathway of molecular action was determined by using enrichment analysis from the predicted targets. what is more, molecular docking also applied to predict the specific binding sites and binding capacity of active compounds and related targets, which validated the results of the compounds-targets network (C-T network). Finally, the mechanism of SFJDC effect on autophagy and virus replication in H1N1 virus-infected RAW264.7 mouse macrophage cells was experimentally verified. RESULTS: The systematic pharmacology results suggested that 68 candidate compounds were obtained from SFJDC, which interacted with 74 different targets related to inflammation and the immune system. The CCK-8 results showed that different concentrations of SFJDC serum had no significant inhibitory effect on the viability of RAW264.7 cells. LC3-II was significantly increased after virus infection compared to the control group, while it was inhibited by different concentrations of SFJDC serum. H1N1 virus nucleocapsid protein (NP protein) was significantly reduced in the high concentration group, Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α), and viral M1 gene were significantly reduced compared to the H1N1 group. CONCLUSIONS: The integrated systemic pharmacological approach and experimental validation not only provide a precise explanation of the molecular mechanism of SFJDC in the treatment of H1N1 infection but also provide valuable clues for the development of novel drug strategies to control the H1N1 infection.

Enrichment of Circulating Tumor Cells of Lung Cancer and Correlation With Serum Leukomonocyte and Tumor Biomarkers: A Retrospective Study.

STUDY DESIGN: Circulating tumor cells is important in the clinical diagnosis of cancer and there are a number of circulating tumor cell detection systems associated with different isolation strategies being validated. There is a novel platform, the CytoBot 2000, which utilizes a combination of physical and immunological technologies to isolate and capture circulating tumor cells. METHODS: In this retrospective study, 39 lung cancer patients and 11 normal healthy individuals were enrolled and performed circulating tumor cell tests and immunofluorescence staining with CytoBot 2000. The performance of this device was assessed by receiver operating characteristic curve. The clinical relevance of circulating tumor cells was assessed by Chi-square. The correlations between circulating tumor cell number and blood lymphocytes and tumor biomarkers were analyzed by Pearson correlation coefficient. RESULTS: The number of circulating tumor cell is significantly increased in lung cancer patients (3.74 > 0.45, P < .0001). The CytoBot 2000 presented a 100% (39/39) circulating tumor cell detection rate in lung cancer patients and 36% (4/11) in healthy individual blood samples, the sensitivity and specificity were 89.7% and 90.9%, respectively, and with the area under curve of 0.966. Further, there was a positive correlation between circulating tumor cell count and carcinoembryonic antigen 211 (R2 = 0.125, P = .027), but not blood lymphocytes (P = .089). CONCLUSIONS: This automatic platform showed excellent performance of circulating tumor cell detection by clinical sample. The tumor biomarkers increased with the number of circulating tumor cell in the lung cancer patients.

Comparison of newly diagnosed COPD patients and the non-COPD residents in Shanghai Minhang District.

Background: To compare whether the general population, especially those without characteristic symptoms, need spirometry screening for chronic obstructive pulmonary disease (COPD). Methods: Residents aged > 40 years old in Minhang, Shanghai, China, filled out screening questionnaires and underwent spirometry. The structured questionnaire integrating COPD population screening and COPD screening questionnaire was designed to obtain data on demographic characteristics, risk factors of COPD, respiratory symptoms, lifestyle habits, and comorbidities. We assessed the correlations between variables and COPD and the impact factors of FEV1% predicted. Results: A total of 1,147 residents were included with a newly diagnosed mild to moderate COPD prevalence of 9.4% (108/1,147); half of the patients (54/108) were asymptomatic. Multivariate analysis did not reveal any significant differences in symptoms or lifestyle factors between newly diagnosed COPD patients and non-COPD participants. However, according to the generalized linear model, older age (ß = -0.062, p < 0.001), male sex (ß = -0.031, p = 0.047), and respiratory symptoms (ß = -0.025, p = 0.013) were associated with more severe airflow limitation. Conclusion: Newly diagnosed COPD patients had few differences compared with the general population, which suggests that a targeted case finding strategy other than general screening was currently preferred. More attention should be paid to respiratory symptoms when making a diagnosis and exploring new therapies and interventions for COPD in the early stage.

Targeted Literature Review of the Burden of Respiratory Syncytial Infection among High-Risk and Elderly Patients in Asia Pacific Region.

INTRODUCTION: The burden of respiratory syncytial virus (RSV), which causes acute respiratory illness, is well recognized among the pediatric population but also imposes a significant risk to the elderly (age ≥ 60) and those with underlying comorbidities. The study aimed to review the most recent data on epidemiology and burden (clinical and economic) of RSV in the elderly/high-risk populations in China, Japan, South Korea, Taiwan, and Australia. METHODS: A targeted review was conducted of English, Japanese, Korean, and Chinese language articles published from 1 January 2010 to 7 October 2020 relevant for the purpose. RESULTS: A total of 881 studies were identified, and 41 were included. The median proportion of elderly patients with RSV in all adult patients with acute respiratory infection (ARI) or community acquired pneumonia was 79.78% (71.43-88.12%) in Japan, 48.00% (3.64-80.00%) in China, 41.67% (33.33-50.00%) in Taiwan, 38.61% in Australia, and 28.57% (22.76-33.33%) in South Korea. RSV was associated with a high clinical burden on those patients with comorbidities such as asthma and chronic obstructive pulmonary disease. In China, inpatients with ARI showed a significantly higher rate of RSV-related hospitalization than outpatients (13.22% versus 4.08%, p < 0.01). The median length of hospital stay among elderly patients with RSV was longest in Japan (30 days) and shortest in China (7 days). Mortality data varied by region with some studies reporting rates as high as 12.00% (9/75) in hospitalized elderly patients. Finally, data on the economic burden was only available for South Korea, with the median cost of a medical admission for an elderly patient with RSV being US dollar (USD) 2933. CONCLUSION: RSV infection is a major source of disease burden among elderly patients, especially in regions with aging populations. It also complicates the management of those with underlying diseases. Appropriate prevention strategies are required to reduce the burden among the adult, especially the elderly, population. Data gaps regarding economic burden of RSV infection in the Asia Pacific region indicates the need for further research to increase our understanding on the burden of this disease in this region.

The Clinical Impact of Metagenomic Next-Generation Sequencing (mNGS) Test in Hospitalized Patients with Suspected Sepsis: A Multicenter Prospective Study.

Background: Metagenomic Next Generation Sequencing (mNGS) has the potential to detect pathogens rapidly. We aimed to assess the diagnostic performance of mNGS in hospitalized patients with suspected sepsis and evaluate its role in guiding antimicrobial therapy. Methods: A multicenter, prospective cohort study was performed. We enrolled patients with suspected sepsis, collected clinical characteristics and blood samples, and recorded the 30-day survival. Diagnostic efficacy of mNGS test and blood culture was compared, and the clinical impact of mNGS on antibiotic regimen modification was analyzed. Results: A total of 277 patients were enrolled, and 162 were diagnosed with sepsis. The mortality was 44.8% (121/270). The mNGS test exhibited shorter turn-out time (27.0 (26.0, 29.0) vs. 96.0 (72.0, 140.3) hours, p < 0.001) and higher sensitivity (90.5% vs. 36.0%, p < 0.001) compared with blood culture, especially for fungal infections. The mNGS test showed better performance for patients with mild symptoms, prior antibiotic use, and early stage of infection than blood culture, and was capable of guiding antibiotic regimen modification and improving prognosis. Higher reads of pathogens detected by mNGS were related to 30-day mortality (p = 0.002). Conclusions: Blood mNGS testing might be helpful for early etiological diagnosis of patients with suspected sepsis, guiding the antibiotic regimen modification and improving prognosis.

PLZF promotes the development of asthma tolerance via affecting memory phenotypes of immune cells.

Clarifying the pathogenesis of asthma and/or identifying the specific pathway underlying oral asthma tolerance (OT) would be of great significance. In our previous study, promyelocytic leukemia zinc finger (PLZF), which reportedly regulates memory phenotypes, was found to promote ovalbumin (OVA)-induced OT. Therefore, this study aimed to explore the regulatory effects of PLZF on memory phenotypes in asthma and OT mouse models. We found that Zbtb16 (encoding PLZF) and PLZF+ cells were highly increased in OT lungs compared with asthmatic lungs. PLZF was co-expressed with GATA3, and IL-4+PLZF+ cells were significantly lower in OT lungs than in asthmatic lungs. Notably, memory cells were decreased in OT mice, and these mice had PLZF+ cells that expressed lower levels of CD44 than those of asthmatic mice. When Zbtb16 was overexpressed in splenic lymphocytes, the number of CD44+ cells decreased. There were increased memory cells in splenic lymphocytes after treatment with the supernatant of OVA-treated airway epithelial cells; however, this was reversed by Zbtb16 overexpression. Early respiratory syncytial virus infection increased memory cells and reduced PLZF+ cells in the OT mice. Collectively, these results indicate that PLZF may reduce the proportion of memory cells, thereby, promoting the establishment of OT.

Genetic evidence on the causality between gut microbiota and various asthma phenotypes: a two-sample Mendelian randomization study.

Introduction: Asthma is a multifarious disease that manifests in various phenotypes. Among the various factors that contribute to the development of asthma, the gut microbiota has recently emerged as a compelling area of investigation. This study aims to investigate the causal relationships between gut microbiota and distinct asthma phenotypes. Methods: The genome-wide association study (GWAS) summary statistics for 211 gut microbial taxa were used as study exposure. Five traits pertaining to various asthma phenotypes (asthma, allergic asthma, childhood asthma, suggestive for eosinophilic asthma and obesity-related asthma) were included as study outcome. We conducted Mendelian randomization (MR) analysis and sensitivity analysis for each bacterial taxa and asthma phenotypes. Result: We discovered a total of 58 associations that exhibited evidence of causality. Out of these, 4 associations remained significant even after applying multiple correction. An increased risk of asthma was causally associated with higher abundance of genus Holdemanella (OR = 1.11; CI: 1.05-1.17; p = 0.027), genus Oxalobacter (OR = 1.09; CI: 1.04-1.15; p = 0.025) and genus Butyricimonas (OR = 1.14; CI: 1.06-1.22; p = 0.027). Order NB1n was causally linked with an increased risk of obesity-related asthma (OR = 1.17; CI: 1.07-1.29; p = 0.015). There was limited overlap among the taxa that exhibited potential causal relationships with distinct asthma phenotypes. Conclusion: Our research has provided genetic evidence that establishes multiple causal relationships between the gut microbiota and distinct asthma phenotypes, supporting the role of the gut microbiota in various asthma phenotypes. It is possible that different taxa play a role in the development of distinct asthma phenotypes. The causal relationships identified in this study require further investigation.

The Establishment of China Bronchiectasis Registry and Research Collaboration (BE-China): Protocol of a prospective multicenter observational study.

BACKGROUND: Bronchiectasis is a highly heterogeneous chronic airway disease with marked geographic and ethnic variations. Most influential cohort studies to date have been performed in Europe and USA, which serve as the examples for developing a cohort study in China where there is a high burden of bronchiectasis. The Establishment of China Bronchiectasis Registry and Research Collaboration (BE-China) is designed to: (1) describe the clinical characteristics and natural history of bronchiectasis in China and identify the differences of bronchiectasis between the western countries and China; (2) identify the risk factors associated with disease progression in Chinese population; (3) elucidate the phenotype and endotype of bronchiectasis by integrating the genome, microbiome, proteome, and transcriptome with detailed clinical data; (4) facilitate large randomized controlled trials in China. METHODS: The BE-China is an ongoing prospective, longitudinal, multi-center, observational cohort study aiming to recruit a minimum of 10,000 patients, which was initiated in January 2020 in China. Comprehensive data, including medical history, aetiological testing, lung function, microbiological profiles, radiological scores, comorbidities, mental status, and quality of life (QoL), will be collected at baseline. Patients will be followed up annually for up to 10 years to record longitudinal data on outcomes, treatment patterns and QoL. Biospecimens, if possible, will be collected and stored at - 80 °C for further research. Up to October 2021, the BE-China has enrolled 3758 patients, and collected 666 blood samples and 196 sputum samples from 91 medical centers. The study protocol has been approved by the Shanghai Pulmonary Hospital ethics committee, and all collaborating centers have received approvals from their local ethics committee. All patients will be required to provide written informed consent to their participation. CONCLUSIONS: Findings of the BE-China will be crucial to reveal the clinical characteristics and natural history of bronchiectasis and facilitate evidence-based clinical practice in China. Trial registration Registration Number in ClinicalTrials.gov: NCT03643653.

Nucleic acid testing of SARS-CoV-2: A review of current methods, challenges, and prospects.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has brought a huge threat to public health and the global economy. Rapid identification and isolation of SARS-CoV-2-infected individuals are regarded as one of the most effective measures to control the pandemic. Because of its high sensitivity and specificity, nucleic acid testing has become the major method of SARS-CoV-2 detection. A deep understanding of different diagnosis methods for COVID-19 could help researchers make an optimal choice in detecting COVID-19 at different symptom stages. In this review, we summarize and evaluate the latest developments in current nucleic acid detection methods for SARS-CoV-2. In particular, we discuss biosensors and CRISPR-based diagnostic systems and their characteristics and challenges. Furthermore, the emerging COVID-19 variants and their impact on SARS-CoV-2 diagnosis are systematically introduced and discussed. Considering the disease dynamics, we also recommend optional diagnostic tests for different symptom stages. From sample preparation to results readout, we conclude by pointing out the pain points and future directions of COVID-19 detection.

Oral antibiotics relieve allergic asthma in post-weaning mice via reducing iNKT cells and function of ADRB2.

The role of normal gut microbiota in asthma or ovalbumin (OVA)-induced asthma tolerance (OT) remains unclear. Here, we established mouse models of asthma and OT followed by 2 weeks of antibiotic treatment, to clear the gut microbiota. Antibiotic treatment was found to alleviate allergic asthma accompanied with a reduction of invariant natural killer (iNKT) cells. By RNA-seq analysis, we found that ß-adrenergic receptor (ADRB) genes, including Adrb1, Adrb2, and Adrb3, were downregulated in asthmatic lungs, but these changes were reversed in OT lungs. Moreover, Adrb2 and Adrb3 were significantly upregulated in asthmatic lungs after antibiotic treatment. Surprisingly, blocking ADRB with propranolol relieved allergic asthma while reducing T helper 2 (Th2) and Treg cell numbers. Further analyses using flow cytometry and immunofluorescence showed that the protein expression level of ADRB2 was higher in asthmatic lungs than that in the control and OT lungs. Notably, dendritic cells (DCs), especially the ADRB2+ DCs, were increased in asthmatic lungs compared to that in the control and OT lungs. In addition, ADRB2+ DCs were significantly reduced following the administration of the ADRB2-specific antagonist ICI118551. Our findings suggest that antibiotic treatment can alleviate OVA-induced allergic asthma via reducing the frequency of iNKT cells and function of ADRB2.

Pulmonary resident memory T cells in respiratory virus infection and their inspiration on therapeutic strategies.

The immune system generates memory cells on infection with a virus for the first time. These memory cells play an essential role in protection against reinfection. Tissue-resident memory T (TRM) cells can be generated in situ once attacked by pathogens. TRM cells dominate the defense mechanism during early stages of reinfection and have gradually become one of the most popular focuses in recent years. Here, we mainly reviewed the development and regulation of various TRM cell signaling pathways in the respiratory tract. Moreover, we explored the protective roles of TRM cells in immune response against various respiratory viruses, such as Respiratory Syncytial Virus (RSV) and influenza. The complex roles of TRM cells against SARS-CoV-2 infection are also discussed. Current evidence supports the therapeutic strategies targeting TRM cells, providing more possibilities for treatment. Rational utilization of TRM cells for therapeutics is vital for defense against respiratory viruses.

Evaluating the ability of the NLHA2 and artificial neural network models to predict COVID-19 severity, and comparing them with the four existing scoring systems.

To improve the identification and subsequent intervention of COVID-19 patients at risk for ICU admission, we constructed COVID-19 severity prediction models using logistic regression and artificial neural network (ANN) analysis and compared them with the four existing scoring systems (PSI, CURB-65, SMARTCOP, and MuLBSTA). In this prospective multi-center study, 296 patients with COVID-19 pneumonia were enrolled and split into the General-Ward-Care group (N = 238) and the ICU-Admission group (N = 58). The PSI model (AUC = 0.861) had the best results among the existing four scoring systems, followed by SMARTCOP (AUC = 0.770), motified-MuLBSTA (AUC = 0.761), and CURB-65 (AUC = 0.712). Data from 197 patients (training set) were analyzed for modeling. The beta coefficients from logistic regression were used to develop a severity prediction model and risk score calculator. The final model (NLHA2) included five covariates (consumes alcohol, neutrophil count, lymphocyte count, hemoglobin, and AKP). The NLHA2 model (training: AUC = 0.959; testing: AUC = 0.857) had similar results to the PSI model, but with fewer variable items. ANN analysis was used to build another complex model, which had higher accuracy (training: AUC = 1.000; testing: AUC = 0.907). Discrimination and calibration were further verified through bootstrapping (2000 replicates), Hosmer-Lemeshow goodness of fit testing, and Brier score calculation. In conclusion, the PSI model is the best existing system for predicting ICU admission among COVID-19 patients, while two newly-designed models (NLHA2 and ANN) performed better than PSI, and will provide a new approach for the development of prognostic evaluation system in a novel respiratory viral epidemic.