Human genetic associations of the airway microbiome in chronic obstructive pulmonary disease.

Little is known about the relationships between human genetics and the airway microbiome. Deeply sequenced airway metagenomics, by simultaneously characterizing the microbiome and host genetics, provide a unique opportunity to assess the microbiome-host genetic associations. Here we performed a co-profiling of microbiome and host genetics with the identification of over 5 million single nucleotide polymorphisms (SNPs) through deep metagenomic sequencing in sputum of 99 chronic obstructive pulmonary disease (COPD) and 36 healthy individuals. Host genetic variation was the most significant factor associated with the microbiome except for geography and disease status, with its top 5 principal components accounting for 12.11% of the microbiome variability. Within COPD individuals, 113 SNPs mapped to candidate genes reported as genetically associated with COPD exhibited associations with 29 microbial species and 48 functional modules (P < 1 × 10-5), where Streptococcus salivarius exhibits the strongest association to SNP rs6917641 in TBC1D32 (P = 9.54 × 10-8). Integration of concurrent host transcriptomic data identified correlations between the expression of host genes and their genetically-linked microbiome features, including NUDT1, MAD1L1 and Veillonella parvula, TTLL9 and Stenotrophomonas maltophilia, and LTA4H and Haemophilus influenzae. Mendelian randomization analyses revealed a potential causal link between PARK7 expression and microbial type III secretion system, and a genetically-mediated association between COPD and increased relative abundance of airway Streptococcus intermedius. These results suggest a previously underappreciated role of host genetics in shaping the airway microbiome and provide fresh hypotheses for genetic-based host-microbiome interactions in COPD.

Low human beta-defensin-2 levels in the sputum of COPD patients are associated with the risk of exacerbations.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a complicated chronic inflammatory disease. It is important to investigate the characteristics of acute exacerbation of COPD to develop new therapeutic strategies. OBJECTIVE: This study aimed to determine the relationship between the human beta-defensin-2 (hBD-2) levels and aggravation of COPD. METHODS: We detected the sputum hBD-2 level of 254 patients from Guangzhou, China, for 2 years. The study participants were categorized into the COPD group (n = 203, GOLD 0-4) and the control group (n = 51, 40-79 years old). At baseline, 12th month, and 24th month, we detected the sputum hBD-2 level and levels of cytokines, such as CXCL10, CXCL11, and IFN. RESULTS: At baseline, there were no significant differences in the sputum and serum hBD-2 levels between the patients and the controls. However, the sputum hBD-2 levels of patients who had at least one symptom aggravation over the next 2 years were significantly lower than those of patients without any exacerbations (1130.9 ± 858.4 pg/mL vs. 2103.7 ± 1294.2 pg/mL, respectively; p = 0.001). Nevertheless, there were no statistically significant differences in the sputum hBD-2 levels between patients (no aggravation history) and controls (2084.9 ± 1317.6 pg/mL vs. 2152.5 ± 1251.6 pg/mL, respectively; p = 0.626). We used a logistic regression model to assess the relationship between aggravation and sputum hBD-2 levels. Interestingly, we found that low hBD-2 level (< 1000 pg/mL) was significantly associated with exacerbations. Specifically, patients with low hBD-2 levels were more likely to experience exacerbations in the next 12 months (0.333 vs. 0.117; p = 0.001). Moreover, we compared the hBD-2 levels between controls and patients with GOLD 3-4 and found that participants with bacteria (+) and/or viruses (+) had an association between hBD-2 level and disease severity (p = 0.02). CONCLUSION: Patients at risk of exacerbations are more likely to have lower sputum hBD-2 levels. These results have important implications for future therapies for COPD.

Effect of the COVID-19 Pandemic on Resilience Among Chinese Adolescents and Its Influential Factors: A Longitudinal Study.

The current study assessed the effect of the coronavirus disease 2019 (COVID-19) pandemic on resilience among Chinese adolescents and explored its influential factors. A total of 2,359 students were recruited from three middle schools through cluster randomization in Chengdu. Data were collected before and after home confinement due to the COVID-19 pandemic. Resilience, family function, and effect of the pandemic were measured using subscales of the Chinese Positive Youth Development Scale, Chinese Family Assessment Instrument, and Children's Revised Impact of Event Scale. Paired samples t test showed resilience decreased significantly after confinement. According to stepwise multiple linear regression, basal resilience, family dysfunction, higher frequencies of hyperarousal symptoms of posttraumatic stress, increased electronic device use, and relationship with caregivers were independent influential factors of resilience. COVID-19 negatively affected adolescents' resilience; therefore, stakeholders need to focus on improving resilience in this population to mitigate mental health impacts of acute stressful events. [Journal of Psychosocial Nursing and Mental Health Services, 60(12), 31-37.].

Differential expression of sputum and serum autoantibodies in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a complex and progressive respiratory disease. Autoimmune processes have been hypothesized to contribute to disease progression; however, the presence of autoantibodies in the serum has been variable. Given that COPD is a lung disease, we sought to investigate whether autoantibodies in sputum supernatant would better define pulmonary autoimmune processes. Matched sputum and serum samples were obtained from the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study and at the Guangzhou Institute of Respiratory Health (GIRH). Samples were collected from patients with varying severity of COPD, asymptomatic smokers, and healthy control subjects. IgG and IgM autoantibodies were detected in sputum and serum of all subjects in both cohorts using a broad-spectrum autoantigen array. No differences were observed in sputum autoantibodies between COPD and asymptomatic smokers in either cohort. In contrast, 16% of detectable sputum IgG autoantibodies were decreased in subjects with COPD compared to healthy controls in the ADEPT cohort. Compared to asymptomatic smokers, approximately 13% of detectable serum IgG and 40% of detectable serum IgM autoantibodies were differentially expressed in GIRH COPD subjects. Of the differentially expressed specificities, anti-nuclear autoantibodies were predominately decreased. A weak correlation between increased serum IgM anti-tissue autoantibodies and a measure of airspace enlargement was observed. The differential expression of specificities varied between the cohorts. In closing, using a comprehensive autoantibody array, we demonstrate that autoantibodies are present in subjects with COPD, asymptomatic smokers, and healthy controls. Cohorts displayed high levels of heterogeneity, precluding the utilization of autoantibodies for diagnostic purposes.

Parotitis due to Burkholderia cepacia infection after autologous hematopoietic stem cell transplantation.

Burkholderia cepacia predominantly causes opportunistic infections in hospitalized and immunocompromised patients such as patients with cystic fibrosis, cancer, or human immunodeficiency virus (HIV). Nonetheless, Burkholderia cepacia is infrequently reported to cause infection in hematopoietic stem cell transplantation (HSCT) recipients. Herein, we report a rare case of suppurative parotitis in a 31-year-old patient with T-cell lymphoblastic lymphoma (T-LBL) who underwent auto-HSCT. The secretion from the Stensen duct was collected, and Burkholderia cepacia was detected using the VITEK-2 identification system. Additionally, sensitive antibiotic therapy against this bacterium was also effective. This is the first case of parotitis triggered by Burkholderia cepacia after auto-HSCT, and it is also the first reported domestic case. This case emphasizes the importance of considering bacterial infections in general and Burkholderia cepacia specifically in HSCT patients with post-transplant parotitis.

NDRG2 mRNA levels and miR-28-5p and miR-650 activity in chronic lymphocytic leukemia.

BACKGROUND: NDRG2 is identified as a tumor suppressor gene in many tumors, and functions in cell proliferation, differentiation and apoptosis. Recent data indicate that NDRG2 expression is up-regulated by TP53. Moreover, proposed mechanisms of NDRG2 inactivation include epigenetic silencing of the NDRG2 promoter and down-regulation by microRNAs (miRNAs). However, few studies have ever been done on the role of NDRG2 and the NDRG2-regulating miRNAs interference in chronic lymphocytic leukemia (CLL). METHODS: NDRG2 and microRNAs mRNA levels in CLL subjects were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The dual-luciferase reporter assay was performed to determine NDRG2-related miRNAs. Low expression of mature exogenous miRNAs in CLL cells was established by transient transfection. NDRG2 protein levels in CLL cells were detected by western blot. In addition, flow cytometry was conducted to examine the apoptosis of CLL cells. RESULTS: Lower expression of NDRG2 was found in the B-cells from 102 CLL patients compared the 40 normal subjects (P < 0.001). Patients with advanced Binet stage (P = 0.001), high lactate dehydrogenase (LDH) level (P = 0.036), un-mutated immunoglobulin heavy chain variable region gene (IGHV) (P = 0.004) and those with p53 aberrations (P < 0.001) had a markedly lower levels of NDRG2 mRNA. This decrease was associated with briefer time-to-treatment (P = 0.001) and poorer survival (P < 0.001). High expression of miR-28-5p and miR-650 was associated with Binet B/C stage (P = 0.044) and IGHV un-mutated (P = 0.011), as well as Binet B/C stage (P = 0.013) and p53 aberrations (P = 0.037), respectively. Inhibition of miR-28-5p or miR-650 could induce more apoptosis in CLL cells with germline TP53. CONCLUSIONS: NDRG2 mRNA levels might be a useful prognostic variable for patients of CLL and up-regulating NDRG2 transcription may be a therapy approach in CLL without p53 aberrations.

GATA3 expression in clinically useful groups of breast carcinoma: a comparison with GCDFP15 and mammaglobin for identifying paired primary and metastatic tumors.

GATA3 has been recognized as the novel marker for identifying primary and metastatic breast carcinomas, consistently showing that GATA3 was significantly more sensitive than traditional markers gross cystic disease fluid protein 15 (GCDFP15) and mammaglobin (MGB). However, clinically useful groups of breast carcinomas status were not identified, which were determining appropriate treatment strategy, affecting the prognosis. In this study, we undertook a comparative study of the marker GATA3 and GCDFP15 and MGB in clinically useful groups of paired primary and metastatic breast cancer. We retrieved 64 cases of matched primary and metastatic breast cancer from the surgical pathology archive at our institution. According to the emerging 2015 St. Gallen Consensus, the clinically useful groups were divided into ER and/or PR (+), HER2 (-), abbreviated as A; ER and/or PR (+), HER2 (+), abbreviated as B; ER and PR (-), HER2 (+), abbreviated as C; ER, PR and HER2 (-), abbreviated as D; each group contained 16 cases (n=16). Tissue microarrays were created, with three 1-mm punch specimens from each case. The tissue microarrays were cut at 4-µm thickness and stained with monoclonal antibodies to GATA3, GCDFP15, and MGB. Staining intensity (0-3+) and extent (0%-100%) were scored with an H-score calculated (range, 0-300). Sensitivities by varying H-score cutoffs (any; ≥50; ≥150) for a positive result in the clinically useful groups of matched primary or metastatic breast cancer among GATA3, GCDFP15, and MGB. GATA3 was significantly more sensitive than GCDFP15 and MGB A and B groups (P<.05) rather than C and D groups (P>.05). However, GATA3 in conjunction with GCDFP15 and MGB detection could improve the sensitivity of C group (P<.05) rather than D group (P>.05). Significantly, good coincidence was observed between primary and metastatic tumor GATA3 expression (κ value = 0.826 >0.75) as compared with the coincidence of GCDFP15 (κ value =0.492 <0.75) and MGB (κ value =0.593 <0.75) (both P<.05). In conclusion, GATA3 expression did not show the same sensitivity for the clinically useful groups of breast cancer. GATA3 expression is positively correlated with ER-positive, PR-positive, and HER2-positive carcinomas. In addition, the matched primary and metastatic tumor expression of GATA3 shows good coincidence. We propose the careful selection of GATA3 for identifying hormone receptor negativity of breast cancer, especially in the case of triple-negative breast cancer.

Distinguishing EGFR mutation molecular subtypes based on MRI radiomics features of lung adenocarcinoma brain metastases.

OBJECTIVE: To explore the feasibility of identifying epidermal growth factor receptor (EGFR) mutation molecular subtypes in primary lesions based on the radiomics features of lung adenocarcinoma brain metastases using magnetic resonance imaging (MRI). METHODS: We retrospectively analyzed clinical, imaging, and genetic testing data of patients with lung adenocarcinoma with EGFR gene mutations who had brain metastases. Three-dimensional radiomics features were extracted from contrast-enhanced T1-weighted images. The volume of interest was delineated and normalized using Z-score, dimensionality reduction was performed using principal component analysis, feature selection using Relief, and radiomics model construction using adaptive boosting as a classifier. Data were randomly divided into training and testing datasets at an 8:2 ratio. Five-fold cross-validation was conducted in the training set to select the optimal radiomics features and establish a predictive model for distinguishing between exon 19 deletion (19Del) and exon 21 L858R point mutation (21L858R), the two most common EGFR gene mutations. The testing set was used for external validation of the models. Model performance was evaluated using receiver operating characteristic curve and decision curve analyses. RESULTS: Overall, 86 patients with 228 brain metastases were included. Patient age was identified as an independent predictor for distinguishing between 19Del and 21L858R. The area under the curve (AUC) values of the radiomics model in the training and testing datasets were 0.895 (95% confidence interval [CI]: 0.850-0.939) and 0.759 (95% CI: 0.0.614-0.903), respectively. The AUC for diagnosis of all cases using a combined model of age and radiomics was 0.888 (95% CI: 0.846-0.930), slightly higher than that of the radiomics model alone (0.866, 95% CI: 0.820-0.913), but without statistical significance (p=0.1626). In the decision curve analysis, both models demonstrated clinical net benefits. CONCLUSIONS: The radiomics model based on MRI of lung adenocarcinoma brain metastases could distinguish between EGFR 19Del and 21L858R mutations in the primary lesion.

[Clinical Characteristics of CD4-CD56+ Blastic Plasmacytoid Dendritic Cell Neoplasm].

OBJECTIVE: To explore the clinical manifestations, pathological features, immunophenotype, as well as diagnosis, treatment and prognosis of patients with CD4-CD56+ blastic plasmacytoid dendritic cell neoplasm (BPDCN), in order to further understand the rare disease. METHODS: The clinical data, laboratory examinations and treatment regimens of two patients with CD4-CD56+ BPDCN in the First Affiliated Hospital of Wannan Medical College were retrospectively analyzed. RESULTS: The two patients were both elderly males with tumor involved in skin, bone marrow, lymph nodes, etc. Immunohistochemical results of skin lesions showed that both CD56 and CD123 were positive, while CD4, CD34, TdT, CD3, CD20, MPO and EBER were negative. Flow cytometry of bone marrow demonstrated that CD56, CD123, and CD304 were all positive, while specific immune markers of myeloid and lymphoid were negative. Two patients were initially very sensitive to acute lymphoblastic leukemia or lymphomatoid chemotherapy regimens, but prone to rapid relapse. The overall survival of both patients was 36 months and 4 months, respectively. CONCLUSION: CD4-CD56+ BPDCN is very rare and easily misdiagnosed as other hematological tumors with poor prognosis. Acute lymphoblastic leukemia or lymphomatoid therapy should be used first to improve the poor prognosis.

Marital adjustment and depressive symptoms among Chinese perinatal women: a prospective, longitudinal cross-lagged study.

OBJECTIVES: The objective was to assess the prevalence of perinatal depressive symptoms and determine the trajectories of marital adjustment and depressive symptoms and their reciprocal relationships among Chinese perinatal women. DESIGN: This was a prospective, longitudinal cross-lagged study. SETTING: The study was conducted at the outpatient department of the largest women's and children's hospital in China, which is located in Chengdu, Sichuan Province. PARTICIPANTS: Four hundred and sixty-three mothers were conveniently sampled. MAIN OUTCOME MEASURES: The Dyadic Adjustment Scale and the Chinese version of the Edinburgh Postnatal Depression Scale were used to evaluate marital adjustment and depressive symptoms, respectively, at three time points: the first trimester of pregnancy (T1), the third trimester of pregnancy (T2) and 6 weeks after childbirth (T3). Descriptive statistics were used to assess the prevalence of perinatal depressive symptoms, and repeated-measures analysis of variance (ANOVA) was used to determine the trajectories of marital adjustment and depressive symptoms among the participants. A cross-lagged model was used to explore the reciprocal relationship between marital adjustment and depressive symptoms. RESULTS: The prevalence of perinatal depressive symptoms among our participants ranged from 21.2% to 24.0%. Repeated-measures ANOVA showed that during the perinatal period there was a significant tendency towards worse marital adjustment (F=33.031, p=0.000) and a slight but not significant reduction in depressive symptoms (F=1.883, p=0.153) among the participants. The cross-lagged model showed that maternal marital adjustment at T1 significantly and negatively predicted depressive symptoms at T2 (ß=-0.165, p<0.001), and that depressive symptoms at T2 significantly and negatively predicted marital adjustment at T3 (ß=-0.135, p<0.001). However, the predictive effects of depressive symptoms at T1 on marital adjustment at T2 and that of marital adjustment at T2 on depressive symptoms at T3 were not significant. CONCLUSION: The prevalence of perinatal depressive symptoms ranged from 21.2% to 24.0% among the participants. During the perinatal period, the marital adjustment of women tended to be worse; however, there was no significant change in depressive symptoms. This study showed that better marital adjustment at T1 was a protective factor against maternal depressive symptoms at T2, and a higher level of depressive symptoms at T2 was a risk factor for worse marital adjustment at T3.

Combined scRNAseq and Bulk RNAseq Analysis to Reveal the Dual Roles of Oxidative Stress-Related Genes in Acute Myeloid Leukemia.

Background: Oxidative stress (OS) can either lead to leukemogenesis or induce tumor cell death by inflammation and immune response accompanying the process of OS through chemotherapy. However, previous studies mainly focus on the level of OS state and the salient factors leading to tumorigenesis and progression of acute myeloid leukemia (AML), and nothing has been done to distinguish the OS-related genes with different functions. Method: First, we downloaded single-cell RNA sequencing (scRNAseq) and bulk RNA sequencing (RNAseq) data from public databases and evaluated the oxidative stress functions between leukemia cells and normal cells by the ssGSEA algorithm. Then, we used machine learning methods to screen out OS gene set A related to the occurrence and prognosis of AML and OS gene set B related to treatment in leukemia stem cells (LSCs) like population (HSC-like). Furthermore, we screened out the hub genes in the above two gene sets and used them to identify molecular subclasses and construct a model for predicting therapy response. Results: Leukemia cells have different OS functions compared to normal cells and significant OS functional changes before and after chemotherapy. Two different clusters in gene set A were identified, which showed different biological properties and clinical relevance. The sensitive model for predicting therapy response based on gene set B demonstrated predictive accuracy by ROC and internal validation. Conclusion: We combined scRNAseq and bulk RNAseq data to construct two different transcriptomic profiles to reveal the different roles of OS-related genes involved in AML oncogenesis and chemotherapy resistance, which might provide important insights into the mechanism of OS-related genes in the pathogenesis and drug resistance of AML.

[Clinical Anslysis of Primary Adrenal NK/T-Cell Lymphoma].

OBJECTIVE: To investigate the clinical characteristics, diagnosis, and treatment of one patient with primary adrenal natural killer/T-cell lymphoma (PANKTCL), and to strengthen the understanding of this rare type of lymphoma. METHODS: The clinical manifestations, diagnosis and treatment process, and prognosis of the patient admitted in our hospital were retrospectively analyzed. RESULTS: Combined with pathology, imaging, bone marrow examination， etc, the patient was diagnosed with PANKTCL (CA stage, stage II; PINK-E score 3, high-risk group). Six cycles of "P-GemOx+VP-16" regimen（gemcitabine 1 g/m2 d1 + oxaliplatin 100 mg/m2 d 1 + etoposide 60 mg/m2 d 2-4 + polyethylene glycol conjugated asparaginase 3 750 IU d 5） was performed, and complete response was assessed in 4 cycles. Maintenance therapy with sintilimab was administered after the completion of chemotherapy. Eight months after the complete response, the patient experienced disease recurrence and underwent a total of four courses of chemotherapy, during which hemophagocytic syndrome occurred. The patient died of disease progression 1 month later. CONCLUSION: PANKTCL is rare, relapses easily, and has a worse prognosis. The choice of the "P-GemOx+VP-16" regimen combined with sintilimab help to improve the survival prognosis of patient with non-upper aerodigestive tract natural killer /T-cell lymphoma.

Efficacy and Safety of Sevelamer Carbonate in Chinese Nondialysis Chronic Kidney Disease Patients with Hyperphosphatemia: A Randomized, Double-Blind, Parallel-Group Study.

Introduction: Previous studies suggested that sevelamer carbonate is well tolerated with a favorable efficacy and safety profile in both dialysis and nondialysis patients in Europe; however, the efficacy remains controversial, and few studies have examined sevelamer carbonate therapy in other ethnic nondialysis CKD patients. This study assessed the efficacy and safety of sevelamer carbonate in Chinese nondialysis CKD patients with hyperphosphatemia. Methods: The multicenter, randomized, double-blind, parallel-group, placebo-controlled, and phase 3 clinical trial enrolled 202 Chinese nondialysis CKD patients with serum phosphorus ≥1.78 mmol/L. Patients were randomly assigned 1:1 to receive sevelamer carbonate (2.4-12 g per day) or placebo for 8 weeks. The primary outcome was the change in serum phosphorous between baseline and week 8. Results: Totally 482 Chinese patients were screened and 202 were randomized (sevelamer carbonate, n = 101; placebo, n = 101). The mean serum phosphorous decreased significantly in patients treated with sevelamer carbonate compared with placebo (-0.22 ± 0.47 vs. 0.05 ± 0.44 mmol/L, p < 0.0001). Significantly (p < 0.0001), decreases of serum total cholesterol, low-density lipoprotein cholesterol, and calcium-phosphorus (Ca × P) product levels from baseline to week 8 were shown in sevelamer carbonate group compared with placebo group. Serum intact parathyroid hormone was not significantly changed in the sevelamer carbonate group (p = 0.83). Patients in the sevelamer carbonate group experienced similar adverse events as the placebo group. Conclusion: Sevelamer carbonate is an effective and well-tolerated phosphate binder in advanced nondialysis CKD Chinese patients with hyperphosphatemia.

Airway dysbiosis accelerates lung function decline in chronic obstructive pulmonary disease.

Progressive lung function decline is a hallmark of chronic obstructive pulmonary disease (COPD). Airway dysbiosis occurs in COPD, but whether it contributes to disease progression remains unknown. Here, we show, through a longitudinal analysis of two cohorts involving four UK centers, that baseline airway dysbiosis in COPD patients, characterized by the enrichment of opportunistic pathogenic taxa, associates with a rapid forced expiratory volume in 1 s (FEV1) decline over 2 years. Dysbiosis associates with exacerbation-related FEV1 fall and sudden FEV1 fall at stability, contributing to long-term FEV1 decline. A third cohort in China further validates the microbiota-FEV1-decline association. Human multi-omics and murine studies show that airway Staphylococcus aureus colonization promotes lung function decline through homocysteine, which elicits a neutrophil apoptosis-to-NETosis shift via the AKT1-S100A8/A9 axis. S. aureus depletion via bacteriophages restores lung function in emphysema mice, providing a fresh approach to slow COPD progression by targeting the airway microbiome.

Correlations of Computed Tomography Measurement of Distal Pulmonary Vascular Pruning with Airflow Limitation and Emphysema in COPD Patients.

Background: Pulmonary vascular alteration is an important feature of chronic obstructive pulmonary disease (COPD), which is characterized by distal pulmonary vascular pruning in angiography. We aimed to further investigate the clinical relevance of pulmonary vasculature in COPD patients using non-contrast computed tomography (CT). Methods: Seventy-one control subjects and 216 COPD patients completed the questionnaires, spirometry, and computed tomography (CT) scans within 1 month and were included in the study. Small pulmonary vessels represented by percentage of cross-sectional area of pulmonary vessels smaller than 5 mm2 or 5-10 mm2 to the total lung fields (%CSA<5 or %CSA5-10, respectively) were measured using ImageJ software. Spearman correlation was used to investigate the relationship between %CSA<5 and airflow limitation. A receiver operating characteristic (ROC) curve was built to evaluate the value of %CSA<5 in discriminating COPD patients from healthy control subjects. Segmented regression was used to analyze the relationship between %CSA<5 and %LAA-950 (percentage of low-attenuation areas less than -950 HU). Results: We found a significant correlation between %CSA<5 and forced expiratory volume in one second (FEV1) percentage of predicted value (%pred) (r = 0.564, P < 0.001). The area under the ROC curve for the value of %CSA<5 in distinguishing COPD was 0.816, with a cut-off value of 0.537 (Youden index J, 0.501; sensitivity, 78.24%; specificity, 71.83%). Since the relationship between %CSA<5 and %LAA-950 was not constant, performance of segmented regression was better than ordinary linear regression (adjusted R2, 0.474 vs 0.332, P < 0.001 and P < 0.001, respectively). As %CSA<5 decreased, %LAA-950 slightly increased until an inflection point (%CSA<5 = 0.524) was reached, after which the %LAA-950 increased apparently with a decrease in %CSA<5. Conclusion: %CSA<5 was significantly correlated with both airflow limitation and emphysema, and we identified an inflection point for the relationship between %CSA<5 and %LAA-950.

Inflammatory Endotype-Associated Airway Resistome in Chronic Obstructive Pulmonary Disease.

Antimicrobial resistance is a global concern in chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD). The collection of antibiotic resistance genes or resistome in human airways may underlie the resistance. COPD is heterogeneous, and understanding the airway resistome in relation to patient phenotype and endotype may inform precision antibiotic therapy. Here, we characterized the airway resistome for 94 COPD participants at stable disease. Among all demographic and clinical factors, patient inflammatory endotype was associated with the airway resistome. There were distinct resistome profiles between patients with neutrophilic or eosinophilic inflammation, two primary inflammatory endotypes in COPD. For neutrophil-predominant COPD, the resistome was dominated by multidrug resistance genes. For eosinophil-predominant COPD, the resistome was diverse, with an increased portion of patients showing a macrolide-high resistome. The differential antimicrobial resistance pattern was validated by sputum culture and in vitro antimicrobial susceptibility testing. Ralstonia and Pseudomonas were the top contributors to the neutrophil-associated resistome, whereas Campylobacter and Aggregatibacter contributed most to the eosinophil-associated resistome. Multiomic analyses revealed specific host pathways and inflammatory mediators associated with the resistome. The arachidonic acid metabolic pathway and matrix metallopeptidase 8 (MMP-8) exhibited the strongest associations with the neutrophil-associated resistome, whereas the eosinophil chemotaxis pathway and interleukin-13 (IL-13) showed the greatest associations with the eosinophil-associated resistome. These results highlight a previously unrecognized link between inflammation and the airway resistome and suggest the need for considering patient inflammatory subtype in decision-making about antibiotic use in COPD and broader chronic respiratory diseases. IMPORTANCE Antibiotics are commonly prescribed for both acute and long-term prophylactic treatment in chronic airway disorders, such as chronic obstructive pulmonary disease (COPD), and the rapid growth of antibiotic resistance is alarming globally. The airway harbors a diverse collection of microorganisms known as microbiota, which serve as a reservoir for antibiotic resistance genes or the resistome. A comprehensive understanding of the airway resistome in relation to patient clinical and biological factors may help inform decisions to select appropriate antibiotics for clinical therapies. By deep multiomic profiling and in vitro phenotypic testing, we showed that inflammatory endotype, the underlying pattern of airway inflammation, was most strongly associated with the airway resistome in COPD patients. There were distinct resistome profiles between neutrophil-predominant and eosinophil-predominant COPD that were associated with different bacterial species, host pathways, and inflammatory markers, highlighting the need of considering patient inflammatory status in COPD antibiotic management.

Multi-omics analyses of airway host-microbe interactions in chronic obstructive pulmonary disease identify potential therapeutic interventions.

The mechanistic role of the airway microbiome in chronic obstructive pulmonary disease (COPD) remains largely unexplored. We present a landscape of airway microbe-host interactions in COPD through an in-depth profiling of the sputum metagenome, metabolome, host transcriptome and proteome from 99 patients with COPD and 36 healthy individuals in China. Multi-omics data were integrated using sequential mediation analysis, to assess in silico associations of the microbiome with two primary COPD inflammatory endotypes, neutrophilic or eosinophilic inflammation, mediated through microbial metabolic interaction with host gene expression. Hypotheses of microbiome-metabolite-host interaction were identified by leveraging microbial genetic information and established metabolite-human gene pairs. A prominent hypothesis for neutrophil-predominant COPD was altered tryptophan metabolism in airway lactobacilli associated with reduced indole-3-acetic acid (IAA), which was in turn linked to perturbed host interleukin-22 signalling and epithelial cell apoptosis pathways. In vivo and in vitro studies showed that airway microbiome-derived IAA mitigates neutrophilic inflammation, apoptosis, emphysema and lung function decline, via macrophage-epithelial cell cross-talk mediated by interleukin-22. Intranasal inoculation of two airway lactobacilli restored IAA and recapitulated its protective effects in mice. These findings provide the rationale for therapeutically targeting microbe-host interaction in COPD.

Risk and survival of second primary malignancies following diagnosis of gastric mucosa-associated lymphoid tissue lymphomas: A population-based study.

Whether gastric mucosa-associated lymphoid tissue lymphoma (GML) is associated with a higher risk of second primary malignancy (SPM) remains controversial. This study aimed to evaluate the detailed risk of SPM and its prognosis in patients with GML based on a large population-based cohort. The Surveillance, Epidemiology, and End Results database was searched to identify patients who were diagnosed with GML during 2000-2014. The standardized incidence ratio was used to estimate the relative risk of developing SPM. Overall survival was evaluated using the Kaplan-Meier method with the log-rank test, as well as Cox regression analysis. Among 3,379 patients with GML, 416 patients (12.31%) developed SPMs. Compared to the general US population, GML patients had a significantly increased risk of developing SPM (standardized incidence ratio: 1.46, 95% CI: 1.33-1.61). The SPM sites were stomach, lung and bronchus, small intestine, thyroid, mouth, and non-Hodgkin's lymphoma. The risk of developing SPM in GML patients varied according to clinical and demographic characteristics. Patients with younger age (<50 year), chemotherapy use and radiotherapy use had the higher risk of developing SPMs. Relative to patients with only GML, GML patients who developed the SPMs had significantly poorer overall survival (P < 0.001). Among GML patients with SPMs, poor overall survival was independently associated with non-localized SPM disease, shorter latency period (<60 months), chemotherapy use and older age (≥70 year). Patients with GML had an elevated risk of developing SPM, which was associated with a poor prognosis. These findings may be useful for improving follow-up surveillance for patients with GML.

The clinical significance of neutrophil-lymphocyte ratio in patients treated with hemodialysis complicated with lung infection.

ABSTRACT: The goal of this work was to investigate the potential significance of neutrophil-lymphocyte ratio (NLR) in patients treated with maintenance hemodialysis (MHD).Herein, we retrospectively reviewed the electronic medical records of 100 patients with end-stage renal failure who were treated with MHD. All patients enrolled in this study met the inclusion criteria and were followed. The differences in each indicator between the two groups were compared using the Wilcoxon rank-sum test. On the other hand, Spearman correlation and logistic regression analysis were used to explore the correlation and risk factors for pulmonary infection between NLR and other indicators. Finally, we determined the optimal cut-off values for NLR, hypersensitive c-reactive protein (hs-CRP), and procalcitonin (PCT) diagnosis of pulmonary infection using the receiver operating characteristic curve.We found that NLR was positively correlated with age, PCT, hs-CRP, and hospital stay, but negatively correlated with hemoglobin, red blood cell, and Albumin. The expression levels of PCT, hs-CRP, and NLR in the infected group decreased significantly than those before treatment. Multiple regression analysis revealed that NLR is an important independent risk factor for MHD patients with pulmonary infection. Additionally, receiver operating characteristic curve analysis showed that the sensitivity, specificity, and area under the curve were 87.76%, 100%, and 0.920 when using NLR combined with hs-CRP to predict pulmonary infection in MHD patients, whereas that of NLR combined with PCT were 87.76%, 96.08%, and 0.944, respectively.Findings from this study suggested that NLR is an independent risk factor for MHD patients with pulmonary infection, which can effectively predict pulmonary infection. Moreover, sensitivity and specificity were greatly enhanced when using NLR combined with PCT/hs-CRP to predict pulmonary infection in MHD patients.