Iron-related gene mutations driving global Mycobacterium tuberculosis transmission revealed by whole-genome sequencing.

BACKGROUND: Iron plays a crucial role in the growth of Mycobacterium tuberculosis (M. tuberculosis). However, the precise regulatory mechanism governing this system requires further elucidation. Additionally, limited studies have examined the impact of gene mutations related to iron on the transmission of M. tuberculosis globally. This research aims to investigate the correlation between mutations in iron-related genes and the worldwide transmission of M. tuberculosis. RESULTS: A total of 13,532 isolates of M. tuberculosis were included in this study. Among them, 6,104 (45.11%) were identified as genomic clustered isolates, while 8,395 (62.04%) were classified as genomic clade isolates. Our results showed that a total of 12 single nucleotide polymorphisms (SNPs) showed a positive correlation with clustering, such as Rv1469 (ctpD, C758T), Rv3703c (etgB, G1122T), and Rv3743c (ctpJ, G676C). Additionally, seven SNPs, including Rv0104 (T167G, T478G), Rv0211 (pckA, A302C), Rv0283 (eccB3, C423T), Rv1436 (gap, G654T), ctpD C758T, and etgB C578A, demonstrated a positive correlation with transmission clades across different countries. Notably, our findings highlighted the positive association of Rv0104 T167G, pckA A302C, eccB3 C423T, ctpD C758T, and etgB C578A with transmission clades across diverse regions. Furthermore, our analysis identified 78 SNPs that exhibited significant associations with clade size. CONCLUSIONS: Our study reveals the link between iron-related gene SNPs and M. tuberculosis transmission, offering insights into crucial factors influencing the pathogenicity of the disease. This research holds promise for targeted strategies in prevention and treatment, advancing research and interventions in this field.

Associations of residential greenness exposure and ambient air pollutants with newly-diagnosed drug-resistant tuberculosis cases.

Growing evidence has found the health protective effects of greenness exposure on tuberculosis (TB) and the impact of ambient air pollutants on TB drug-resistance. However, it remains unclear whether residential greenness is also beneficial to reduce TB drug-resistance, and whether air pollution modify the greenness-TB resistance relationship. We enrolled 5006 newly-diagnosed TB patients from Shandong, China, during 2014 to 2021. Normalized Difference Vegetation Index (NDVI) in 250 m and 500 m buffer around individuals' residential zone was used to assess greenness exposure. All patients were divided by quartiles of NDVI250-m and NDVI500-m (from low to high: Q1, Q2, Q3, Q4) respectively. Six logistic regression models (NDVI, NDVI + PM2.5/PM10/SO2/NO2/O3) were used to estimate the association of NDVI and TB drug-resistance when adjusting different air pollutants or not. All models were adjusted for age, gender, body mass index, complications, smoking, drinking, population density, nighttime light index, road density. Compared with participants in NDVI250-m Q1 and NDVI500-m Q1, other groups had lower rates of MDR-TB, PDR-TB, RFP-resistance, SM-resistance, RFP + SM resistance, INH + RFP + EMB + SM resistance. NDVI500-m reduced the risk of multidrug resistant tuberculosis (MDR-TB) and the adjusted odds ratio (aOR, 95% confidence interval, CI) compared with NDVI500-m Q1 were 0.736 (0.547-0.991) in NDVI + PM10 model, 0.733 (0.544-0.986) in NDVI + PM2.5 model, 0.735(0.546-0.99) in NDVI + SO2 model, 0.736 (0.546-0.991) in NDVI + NO2 model, respectively, P < 0.05. NDVI500-m contributed to a decreased risk of streptomycin (SM)-resistance. The aOR of rifampicin (RFP) + SM resistance were 0.132 (NDVI250-m, Q4 vs Q1, 95% CI: 0.03-0.578), 0.199 (NDVI500-m, Q3 vs. Q1, 95% CI: 0.057-0.688) and 0.264 (NDVI500-m, Q4 vs. Q1, 95% CI: 0.087-0.799). The adjusted ORs (Q2 vs. Q1, 95% CI) of isoniazid (INH) + RFP + ethambutol (EMB) + SM resistance in 500 m buffer were 0.276 (0.119-0.639) in NDVI model, 0.279 (0.11-0.705) in NDVI + PM10 model, 0.281 (0.111-0.713) in NDVI + PM2.5 model, 0.279 (0.11-0.709) in NDVI + SO2 model, 0.296 (0.117-0.754) in NDVI + NO2 model, 0.294 (0.116-0.748) in NDVI + O3 model, respectively. The study showed, for the first time, that residential greenness exposure in 500 m buffer is beneficial for reducing newly-diagnosed DR-TB (including PDR-RB, MDR-TB, MR-TB), and ambient air pollutants may partially mediate this association.

Identifying optimal first-line immune checkpoint inhibitors based regiments for advanced non-small cell lung cancer without oncogenic driver mutations: A systematic review and network meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have changed the treatment pattern of advanced and metastatic NSCLC. A series of ICI based therapies have emerged in the first-line treatment field, but the comparative efficacy was unclear. METHOD: We searched multiple databases and abstracts of major conference proceedings up to Apri1, 2022 for phase III randomised trials of advanced driver-gene wild type NSCLC patients receiving first-line therapy. Outcomes analyzed included progression free survival (PFS), overall survival (OS), and et al. RESULTS: Thirty-two double-blind RCTs were included, involving 18,656 patients assigned to 22 ICI-based first-line regimens. A series of ICI regiments (including ICI plus chemotherapy), ICI monotherapy, doublet ICIs, doublet ICIs plus chemotherapy) emerged, and showed significant PFS and OS benefit than chemotherapy and chemotherapy + bevacizumab (BEV) for advanced wild-type NSCLC. In comprehensive terms of PFS, chemoimmunotherapy (CIT) were significantly more effective than ICI monotherapy and doublet ICIs. In terms of OS for patients with non-squamous NSCLC, pembrolizumab containing CIT was associated with a median rank of the best regimens, and followed by Atezolizumab+BEV based CIT; while for OS in patients with squamous NSCLC, Cemiplimab and sintilimab based CIT were the most effective regimens. For more than 2 years follow-up, the atezolizumab, pembrolizumab, nivolumab and durvalumab containing ICI therapy all provide a durable long-term OS benefit over chemotherapy and BEV + chemotherapy. CONCLUSIONS: The findings of the present NMA represent the most comprehensive evidence, which might suggest or provide basis for first-line ICI therapy decision for advanced NSCLC patients without oncogenic driver mutations.

Impact of alcohol drinking and tobacco smoking on the drug-resistance of newly diagnosed tuberculosis: a retrospective cohort study in Shandong, China, during 2004-2020.

OBJECTIVES: To investigate the independent and collective impact of alcohol drinking and tobacco smoking on the drug-resistance of newly diagnosed tuberculosis (TB). DESIGN: This was a retrospective cohort study. SETTING: Shandong, China. PARTICIPANTS: Patients with newly diagnosed TB from 1 January 2004 to 31 December 2020 were collected. Exclusive criteria: retreated cases; extrapulmonary tuberculosis; without information on drug susceptibility testing results, smoking or drinking habits; bacteriological identification as non-tuberculous mycobacteria. PRIMARY AND SECONDARY OUTCOME MEASURES: Patients were classified into four groups including smokers only (G1), drinker only (G2), smoker +drinker (G3), non-smoker +non-drinker group (G0). We described the drug-resistant profiles, clinical factors and calculated the ORs of different drug-resistance among G1, G2, G3, compared with G0 through univariate and multivariate logistics regression models. RESULTS: Of the 7996 TB cases enrolled, the proportions of G1, G2, G3 and G0 were 8.25%, 3.89%, 16.46% and 71.40%, respectively. The rates of drug-resistant (DR)-TB, mono-resistant TB, multidrug resistant (MDR)-TB, polydrug resistant TB in G1, G2, G3 and G0 were 19.24%/16.4%/17.33%/19.08%, 11.52%/8.68%/10.94%/11.63%, 3.03%/2.57%/2.96%/3.66% and 4.70%/4.82%/3.34%/ 4.08%, respectively. G3 had a higher risk of MDR1: isoniazid +rifampin (adjusted OR (aOR)=1.91, 95% CI: 1.036 to 3.532), but had a lower risk of DR-TB (aOR=0.84, 95% CI: 0.71 to 0.99), rifampin-related resistance (aOR=0.68, 95% CI: 0.49 to 0.93), streptomycin-related resistance (aOR=0.82, 95% CI: 0.68 to 0.99), ethambutol-related resistance (aOR=0.57, 95% CI: 0.34 to 0.95), MDR3: isoniazid +rifampin+streptomycin (aOR=0.41, 95% CI: 0.19 to 0.85), any isoniazid +streptomycin resistance (aOR=0.85, 95% CI: 0.71 to 1.00). However, there were no significant differences between G1 and G0, G2 and G0 in all drug-resistant subtypes. Those patients with cavity had a higher risk of DR-TB among G3 (OR=1.35, 95% CI: 1.01 to 1.81). CONCLUSION: Although we did not found an independent impact of alcohol drinking or tobacco smoking on TB drug-resistance, respectively, these two habits had a combined effect on TB drug-resistance.

Use of PD-1 inhibitor tislelizumab in the treatment of advanced pulmonary sarcomatoid carcinoma: A case report.

Pulmonary sarcomatoid carcinoma (PSC), characterized by poor differentiation, aggressive progression, and early metastasis, is a rare type of non-small cell lung carcinoma (NSCLC), which shows a low response rate to conventional antitumor therapies and has a poor prognosis. With the achievements in gene sequencing, targeted therapy, and immunotherapy, several new approaches have recently been explored in PSC treatment. A small case series of PSC patients were found to have programmed death-ligand 1 (PD-L1) overexpression, a prerequisite for PD-1 inhibiting therapy, which made immunotherapy possible. However, anti-PD-1 treatment for PSCs was still at a preliminary stage. Here, we report the successful outcome of tislelizumab monotherapy in a patient with advanced PSC with pleural invasion, thus providing a novel promising approach for PSC patients with PD-L1 overexpression.

Risk factors for drug-resistant tuberculosis, the association between comorbidity status and drug-resistant patterns: a retrospective study of previously treated pulmonary tuberculosis in Shandong, China, during 2004-2019.

OBJECTIVE: This study was designed to identify the risk factors for drug-resistant tuberculosis (DR-TB) and the association between comorbidity and drug resistance among retreated pulmonary tuberculosis (PTB). DESIGN: A retrospective study was conducted among all the 36 monitoring sites in Shandong, China, over a 16-year period. Baseline characteristics were collected from the TB Surveillance System. Categorical variables were compared by Fisher's exact or Pearson's χ2 test. The risk factors for drug resistance were identified using univariable analysis and multivariable logistic models. The influence of comorbidity on different types of drug resistance was evaluated by performing multivariable logistic models with the covariates adjusted by age, sex, body mass index, drinking/smoking history and cavity. RESULTS: A total of 10 975 patients with PTB were recorded during 2004-2019, and of these 1924 retreated PTB were finally included. Among retreated PTB, 26.2% were DR-TB and 12.5% had comorbidity. Smoking (adjusted OR (aOR): 1.69, 95% CI 1.19 to 2.39), cavity (aOR: 1.55, 95% CI 1.22 to 1.97) and comorbidity (aOR: 1.44, 95% CI 1.02 to 2.02) were risk factors for DR-TB. Of 504 DR-TB, 9.5% had diabetes mellitus, followed by hypertension (2.0%) and chronic obstructive pulmonary disease (1.8%). Patients with retreated PTB with comorbidity were more likely to be older, have more bad habits (smoking, alcohol abuse) and have clinical symptoms (expectoration, haemoptysis, weight loss). Comorbidity was significantly associated with DR-TB (aOR: 1.44, 95% CI 1.02 to 2.02), overall rifampin resistance (aOR: 2.17, 95% CI 1.41 to 3.36), overall streptomycin resistance (aOR: 1.51, 95% CI 1.00 to 2.27) and multidrug resistance (aOR: 1.96, 95% CI 1.17 to 3.27) compared with pan-susceptible patients (p<0.05). CONCLUSION: Smoking, cavity and comorbidity lead to an increased risk of drug resistance among retreated PTB. Strategies to improve the host's health, including smoking cessation, screening and treatment of comorbidity, might contribute to the control of tuberculosis, especially DR-TB, in China.

Using a risk model for probability of cancer in pulmonary nodules.

BACKGROUND: Considering the high morbidity and mortality of lung cancer and the high incidence of pulmonary nodules, clearly distinguishing benign from malignant lung nodules at an early stage is of great significance. However, determining the kind of lung nodule which is more prone to lung cancer remains a problem worldwide. METHODS: A total of 480 patients with pulmonary nodule data were collected from Shandong, China. We assessed the clinical characteristics and computed tomography (CT) imaging features among pulmonary nodules in patients who had undergone video-assisted thoracoscopic surgery (VATS) lobectomy from 2013 to 2018. Preliminary selection of features was based on a statistical analysis using SPSS. We used WEKA to assess the machine learning models using its multiple algorithms and selected the best decision tree model using its optimization algorithm. RESULTS: The combination of decision tree and logistics regression optimized the decision tree without affecting its AUC. The decision tree structure showed that lobulation was the most important feature, followed by spiculation, vessel convergence sign, nodule type, satellite nodule, nodule size and age of patient. CONCLUSIONS: Our study shows that decision tree analyses can be applied to screen individuals for early lung cancer with CT. Our decision tree provides a new way to help clinicians establish a logical diagnosis by a stepwise progression method, but still needs to be validated for prospective trials in a larger patient population.

Primary Drug-Resistance Pattern and Trend in Elderly Tuberculosis Patients in Shandong, China, from 2004 to 2019.

BACKGROUND: With an aging population, China is facing a huge burden of elderly patients with drug resistant tuberculosis (DR-TB), which has become a significant obstacle for the global TB control. There is still little study on DR-TB in the elderly in China so far. Thus, more research on the epidemiological characteristics and trend of primary DR-TB among the elderly will be necessary. METHODS: A retrospective study was conducted in Shandong, China from 2004 to 2019. We collected 12,661 primary TB cases, of which 4368 elderly (≥60 years) primary TB cases were involved. Clinical characteristics including age, sex, cavity, smoking, drinking, comorbidity and drug susceptibility data were collected from 36 TB prevention and control institutions of Shandong Province. Sputum samples were collected by each surveillance site, and examined in the TB Reference Laboratory of SPCH. Descriptive statistical analysis, chi-square and linear regression were used for analyzing. RESULTS: Among 4368 elderly patients with primary TB, the DR-TB and multi-resistant tuberculosis (MDR-TB) accounted for 17.19% and 2.29%, respectively. During 2004-2019, the proportions of MDR-TB, polydrug resistant tuberculosis (PDR-TB), rifampin (RFP)-resistance increased by 160.00%, 18.18%, 231.82%, respectively and the rate of DR-TB among elderly patients with primary cavitary TB increased by 255%. Among the elderly with primary DR-TB during 2004-2019, the proportion of male (from 85.19 to 89.06), cavity (from 7.41 to 46.88), RFP-resistance (from 3.70 to 21.88), and streptomycin (SM)-resistance (from 37.04 to 62.5) increased significantly (P<0.05). And the proportion of female (from 14.81 to 10.94), non-cavity (from 92.59 to 32.81), INH-resistance (from 66.67 to 57.81) decreased significantly (P<0.05). CONCLUSION: Among the elderly, the proportions of MDR-TB, PDR-TB, RFP-resistance and cavitary DR-TB increased significantly. The pattern of DR-TB changed from female, non-cavity and INH-resistant groups to male, cavity, RFP or SM-resistant groups. For a better control on the elderly DR-TB in the future, we should pay more attention to male, smoking, drinking, chronic obstructive pulmonary disease (COPD) and diabetes subgroups and take targeted measures to control these subgroups.

Unexpected positive correlation between human development index and risk of infections and deaths of COVID-19 in Italy.

In this analysis, we observed that human development index (an integrated index of life expectation, education and living standard) correlates with infection rate (proportion of confirmed cases among the population) and the fatality rate of COVID-19 in Italy based on data as of May 15, 2020. Further analysis showed that HDI is negatively correlated with cigarette consumption, whereas it is positively correlated with chronic disease and average annual gross salary. These factors may partially explain why unexpected positive correlation is observed between human development index and risk of infections and deaths of COVID-19 in Italy.

Primary drug resistance of mycobacterium tuberculosis in Shandong, China, 2004-2018.

BACKGROUND: Primary drug-resistant tuberculosis (DR-TB) has contributed to a significant health and economic burden on a global scale, especially in China. we sought to estimate epidemiological characteristics of primary DR-TB in China from 2004 to 2018. METHODS: Eleven thousand four hundred sixty-seven newly diagnosed and 1981 retreated TB cases with drug susceptibility data were included. Chi-Square test for trends, linear regression, a joinpoint regression model and temporal trend in proportions of the different resistance patterns were carried out. RESULTS: The proportion of primary DR-TB and mono-resistant TB (MR-TB) in China had reduced by more than 12% since 2004, and were 21.38%, 13.35% in 2018 respectively. Among primary DR-TB cases (2173,18.95%), the percentage of multiresistant TB (MDR-TB, from 5.41 to 17.46%), male (from 77.03 to 84.13%), cavity (from 13.51 to 43.92%), rifampicin(RFP)-resistant TB (from 8.11 to 26.98%), streptomycin(SM)-resistant TB (from 50.00 to 71.43%) increased significantly (P < 0.05). On the contrary, the proportion of female, non-cavity, isoniazide(INH)-resistant TB (from 55.41 to 48.15%) and MR-TB (from 82.43 to 62.43%) decreased significant (P < 0.05). The primary drug resistance rate among female, cavity, smoking, drinking, 15 to 44 year-old TB subgroups increased by 0.16, 6.24, 20.95, 158.85, 31.49%, respectively. The percentage of primary DR-TB, RFP-resistant TB dropped significantly during 2004-2007 in Joinpoint regression model. CONCLUSION: The total rate of drug resistance among new TB cases showed a downward trend in Shandong, China, from 2004 to 2018. Primary drug resistance patterns were shifting from female, non-cavity, INH-resistant TB, and MR-TB groups to male, cavity, RFP/SM-resistant TB, and MDR-TB groups. Considering the rising drug resistance rate among some special population, future control of primary DR-TB in China may require an increased focus on female, cavity, smoking, drinking, or 15 to 44 year-old TB subgroups.

The burden of air pollution and weather condition on daily respiratory deaths among older adults in China, Jinan from 2011 to 2017.

The health effects of short-term exposure to air pollutants on respiratory deaths and its modifiers such as meteorological indexes have been widely investigated. However, most of the previous studies are limited to single pollutants or total respiratory deaths, and their findings are inconsistent.To comprehensively examine the short-term effects of air pollutants on daily respiratory mortality.Our analysis included 16,931 nonaccidental respiratory deaths (except lung cancer and tuberculosis) among older adults (>65 years) from 2011 to 2017 in Jinan, China. We used a generalized additive Poisson models adjusted for meteorology and population dynamics to examine the associations between air pollutants (particulate matter with an aerodynamic diameter of b2.5µm [PM2.5], particulate matter with an aerodynamic diameter of b10µm [PM10], SO2, NO2, O3) and daily mortality for the total patients, males, females, chronic airway diseases, pneumonia patients, and rest patients in Jinan.Outdoor air pollution was significantly related to mortality from all respiratory diseases especially from chronic airway disease in Jinan, China. The effects of air pollutants had lag effects and harvesting effects, and the effects estimates usually reached a peak at lag 1 or 2 day. An increase of 10 µg/m or 10 ppb of PM2.5, PM10, SO2, NO2, and O3 corresponds to increments in mortality caused by chronic airway disease of 0.243% (95% confidence interval [CI]: -0.172-0.659) at lag 1 day, 0.127% (95% CI: -0.161-0.415) at lag 1 day, 0.603% (95% CI: 0.069-1.139) at lag 3 day, 0.649% (95% CI: -0.808-2.128) at lag 0 day and 0.944% (95% CI: 0.156-0.1598) at lag 1 day, respectively. The effects of air pollutants were usually greater in females and varied by respiratory subgroups. Spearman correlation analysis suggested that there was a significant association between meteorological indexes and air pollutants.Sex, age, temperature, humidity, pressure, and wind speed may modify the short-term effects of outdoor air pollution on mortality in Jinan. Compared with the other pollutants, O3 had a stronger effect on respiratory deaths among the elderly. Moreover, chronic airway diseases were more susceptible to air pollution. Our findings provided new evidence for new local environmental and health policies making.

PDGF-induced airway smooth muscle proliferation is associated with Human antigen R activation and could be weakened by AMPK activation.

CyclinD1 over-expression is the key pathogenetic event underlying airway smooth muscle (ASM) proliferation. Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein, and is known to regulate the expression of multiple cell cycle regulators. The aim of the study is to investigate whether HuR might also be involved in ASM proliferation. In cultured ASM cells, PDGF treatment induced a significant elevation of HuR expression at both mRNA and protein levels. Immunofluorescence analysis demonstrated PDGF might promote HuR translocation from nucleus to cytoplasma as well. RNA-interference of HuR effectively decreased PDGF-induced cyclinD1 over-expression in ASM cells. Furthermore, AMPK activation by AICAR could effectively decrease PDGF-induced HuR cytoplasmatic translocation, cyclinD1 expression and ASM cells proliferation. In conclusion, altered expression and activity of HuR might participate in PDGF-induced ASM cells cyclinD1 expression and proliferation. The effectiveness of AMPK activation indicated a novel intervention method for airway remodeling.

[Effect and mechanism of arsenic trioxide on chemosensitivity of human lung adenocarcinoma cells].

OBJECTIVE: To study the apoptosis and chemosensitive effect of As(2)O(3) on human lung adenocarcinoma cell line A549. METHODS: MTT colorimetric assay, immunohistochemical method, flow cytometry and RT-PCR were applied to observe the different effects induced by As(2)O(3) with different concentrations on A549 cells. RESULTS: 1, 2 micro mol/L As(2)O(3) increased Fas expression and inhibited the expression of bcl-2, MRP and LRP; G(1) arrest was observed and the cells were more sensitive to cisplatin. A549 cells in the presence of 5 micro mol/L As(2)O(3) showed growth inhibition and up-regulation of bcl-2, MRP and LRP expressions; but their chemosensitivity to cisplatin did not change. CONCLUSION: As(2)O(3) in low concentrations can increase the chemosensitivity of A549 cells by regulating the expression of apoptosis genes, anti-apoptosis genes and drug-resistant genes and affecting the cell cycle progress.

[The relationship between transforming growth factor-beta1, platelet derived growth factor and airway remodeling in eosinophilic bronchitis].

OBJECTIVE: To study the relationship between the expression of transforming growth factor-beta(1) (TGF-beta(1)) and platelet derived growth factor (PDGF) and airway remodeling in eosinophilic bronchitis (EB). METHODS: Bronchial biopsy specimens were obtained from 12 patients with EB (A group), 10 asthmatic patients (B group) and 10 patients (C group) with peripheral lung cancer in early stage. The subepithelial basement membrane (SBM) thickness was measured by light microscopy using HE staining. The expressions of TGF-beta(1) and PDGF in the bronchial mucosa were examined by immunostaining. RESULTS: The SBM of A group [(6.3 +/- 1.4) micro m] was significantly thicker than that of C group [(4.1 +/- 1.2) micro m, P < 0.05], but significantly thinner than that of B group [(8.2 +/- 1.5) micro m]. The numbers of positive cells for TGF-beta(1) and PDGF in A group (59 +/- 9, 47 +/- 7 respectively) and B group (85 +/- 12, 76 +/- 11, respectively) were significantly higher than those in C group (31 +/- 4, 20 +/- 3, respectively), and were positively correlated with SBM thickness (r = 0.76, 0.52, P < 0.05). CONCLUSION: These results suggest that TGF-beta(1) and PDGF expressions in bronchial mucosa may play a role in bronchial subepithelial fibrosis in EB patients.