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FeSO was prepared using an impregnation method, and showed remarkable ozonation catalytic activity for the degradation of sulfamethoxazole, which followed ˙OH production mechanism.

Bacterial lung infections lead to greater than 4 million deaths per year with antibiotic treatments driving an increase in antibiotic resistance and a need to establish new therapeutic approaches. Recently, we have generated mouse and rat stem cell-derived alveolar-like macrophages (ALMs), which like primary alveolar macrophages (1'AMs), phagocytose bacteria and promote airway repair. Our aim was to further characterize ALMs and determine their bactericidal capabilities. The characterization of ALMs showed that they share known 1'AM cell surface markers, but unlike 1'AMs are highly proliferative in vitro. ALMs effectively phagocytose and kill laboratory strains of P. aeruginosa (P.A.), E. coli (E.C.) and S. aureus, and clinical strains of P.A. In vivo, ALMs remain viable, adapt additional features of native 1'AMs, but proliferation is reduced. Mouse ALMs phagocytose P.A. and E.C. and rat ALMs phagocytose and kill P.A. within the lung 24 h post-instillation. In a pre-clinical model of P.A.-induced lung injury, rat ALM administration mitigated weight loss and resolved lung injury observed seven days post-instillation. Collectively, ALMs attenuate pulmonary bacterial infections and promote airway repair. ALMs could be utilized as an alternative or adjuvant therapy where current treatments are ineffective against antibiotic-resistant bacteria or to enhance routine antibiotic delivery.

The zoonotic Lyme neuroborreliosis (LNB) disease is caused by Borrelia burgdorferi, with wide distribution, rapid dissemination and high disability rate. However, the molecular mechanism underlying B. burgdorferi mediated neuroborreliosis remains largely unknown. Here, the frontal cortex from rhesus brains was incubated with B. burgdorferi, and proteomics profiling was evaluated by isobaric tag for relative and absolute quantitation. Proteins were identified and quantified, and differentially expressed proteins (DEPs) were isolated by comparing co-cultured samples and control samples. A total of 43, 164 and 368 DEPs were significantly altered after 6, 12 and 24 h treatment with B. burgdorferi respectively. Gene ontology and KEGG pathway analyses revealed that chemokine biological process was significantly enriched. Two genes in chemokine pathway including GRB2 and ROCK2 were significantly up-regulated after B. burgdorferi co-culturing. By in vitro assay, we confirmed that the expression of GRB2 and ROCK2 was increased after B. burgdorferi infection. In conclusion, our study revealed the involvement of chemokine pathway in the pathogenesis of LNB. GRB2 and ROCK2 may be novel biomarkers and therapeutic targets for LNB.

BackgroundPrecise breast cancer–related mortality forecasts are required for public health program and healthcare service planning. A number of stochastic model–based approaches for predicting mortality have been developed. The trends shown by mortality data from various diseases and countries are critical to the effectiveness of these models. This study illustrates the unconventional statistical method for estimating and predicting the mortality risk between the early-onset and screen-age/late-onset breast cancer population in China and Pakistan using the Lee–Carter model.MethodsLongitudinal death data for female breast cancer from 1990 to 2019 obtained from the Global Burden of Disease study database were used to compare statistical approach between early-onset (age group, 25–49 years) and screen-age/late-onset (age group, 50–84 years) population. We evaluated the model performance both within (training period, 1990–2010) and outside (test period, 2011–2019) data forecast accuracy using the different error measures and graphical analysis. Finally, using the Lee–Carter model, we predicted the general index for the time period (2011 to 2030) and derived corresponding life expectancy at birth for the female breast cancer population using life tables.ResultsStudy findings revealed that the Lee–Carter approach to predict breast cancer mortality rate outperformed in the screen-age/late-onset compared with that in the early-onset population in terms of goodness of fit and within and outside forecast accuracy check. Moreover, the trend in forecast error was decreasing gradually in the screen-age/late-onset compared with that in the early-onset breast cancer population in China and Pakistan. Furthermore, we observed that this approach had provided almost comparable results between the early-onset and screen-age/late-onset population in forecast accuracy for more varying mortality behavior over time like in Pakistan. Both the early-onset and screen-age/late-onset populations in Pakistan were expected to have an increase in breast cancer mortality by 2030. whereas, for China, it was expected to decrease in the early-onset population.ConclusionThe Lee–Carter model can be used to estimate breast cancer mortality and so to project future life expectancy at birth, especially in the screen-age/late-onset population. As a result, it is suggested that this approach may be useful and convenient for predicting cancer-related mortality even when epidemiological and demographic disease data sets are limited. According to model predictions for breast cancer mortality, improved health facilities for disease diagnosis, control, and prevention are required to reduce the disease’s future burden, particularly in less developed countries.

BACKGROUND AND AIMS Epigenetic changes play a role in the occurrence of asthma. In this study, we evaluated the methylation status of glucocorticoid-induced transcript 1 (GLCCI1) and assessed its associations with asthma and asthma severity. MATERIALS AND METHODS Peripheral blood mononuclear cells were harvested from 33 severe asthma patients, 84 mild-moderate asthma patients and 79 healthy controls of Han nationality. GLCCI1 methylation were screened using the MassArray Epityper platform (Agena). We also conducted mRNA sequencing of GLCCI1-knockout mice to further explore possible functions of this gene. RESULTS We found 5 GLCCI1 methylation sites independently correlated with asthma (adjusted p

Background Prostate cancer is the second most frequently diagnosed cancer for males worldwide, but the spatial and temporal trends of prostate cancer burden remain unknown in Asia. This study aimed to investigate the changing spatial and temporal trends of incidence, prevalence, mortality, disability-adjusted life year (DALY), and mortality-to-incidence ratio (MIR) of prostate cancer, and their association with the Socio-Demographic Index (SDI) in 48 Asian countries from 1990 to 2019. Methods Data were extracted from the Global Health Data Exchange query tool, covering 48 Asian countries from 1990 to 2019. The average annual percent change was calculated to evaluate temporal trends. Spatial autocorrelation analysis was used to obtain spatial patterns, and the association between SDI and prostate cancer burden was estimated using a spatial panel model. Results In Asia, the age-standardized incidence and prevalence of prostate cancer increased in almost all countries, and its mortality and DALY also increased in over half of the countries. Significantly regional disparities were found in Asia, and the hot spots for incidence, prevalence, mortality, and DALY were all located in Western Asia, the hot spots of percent change also occurred in Western Asia for incidence and DALY. Furthermore, SDI had a positive association with mortality (coef = 2.51, 95% confidence interval [CI]: 2.13-2.90) and negative association with DALY (coef = -14.99, 95% CI: -20.37 to -9.60) and MIR (coef = -0.95, 95%CI: -0.99 to -0.92). Conclusions Prostate cancer burden increased rapidly throughout Asia and substantial disparities had persisted between countries. Geographically targeted interventions are needed to reduce the prostate cancer burden throughout Asia and in specific countries.

Background Prostate, bladder and kidney cancers are common age-related genitourinary cancers. China's population is aging at an increasing rate, so predicting the morbidity and mortality of prostate, bladder, and kidney cancer in China is of great significance to provide epidemiological evidence for forward planning and implementation of national health policies. Methods Numbers of incidences and deaths by cancer (prostate, bladder and kidney), sex (male and female) and age groups from 1990 to 2019 were extracted from the Global Burden of Disease (GBD) Study. We applied Bayesian age-period-cohort models to predict incidences and deaths to 2030. We also calculated Age-standardized incidence rate (ASIR) and mortality rate (ASMR), their trends were quantified by estimated average percentage change (EAPC) and 95% confidence interval (CI). Results Predictions suggest that by 2030, there will be 315,310 prostate cancer cases, 192,390 bladder cancer cases and 126,980 kidney cancer cases. The ASIRs will increase to 25.54/100,000 for prostate cancer (EAPC: 2.88, 95% CI, 2.84, 2.93), 7.54/100,000 for bladder cancer (EAPC: 2.58, 95% CI, 2.54, 2.61) and 5.63/100,000 for kidney cancer (EAPC: 4.78, 95% CI, 4.54, 5.02). Number of deaths in 2030 will be 81,540, 61,220, and 41,940, respectively. Different ASMR changes are observed, the ASMR for prostate cancer will drop to 7.69/100,000 (EAPC: -0.29, 95% CI, -0.31, -0.27), the ASMR for bladder cancer will stabilize at 2.49/100,000 (EAPC: 0.00, 95% CI, -0.02, 0.03), the ASMR of kidney cancer will increase to 1.84/100,000 (EAPC: 3.45, 95% CI, 3.22, 3.67). From 1990 to 2030, higher numbers of cases and rates are reported among males and in the 60 plus age group, both ASIR and ASMR of bladder and kidney cancers presents progressively widening differences between both males and females and between the Conclusion Morbidity and mortality of the three genitourinary cancers are predicted to increase further over the next decade. It highlights the need for timely development and implementation of optimal health policies to curb the epidemic trends.

Pleural effusion is a common clinical condition caused by several respiratory diseases, including tuberculosis and malignancy. However, rapid and accurate diagnoses of tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) remain challenging. Although monocytes have been confirmed as an important immune cell in tuberculosis and malignancy, little is known about the role of monocytes subpopulations in the diagnosis of pleural effusion.Pleural effusion samples and peripheral blood samples were collected from 40 TPE patients, 40 MPE patients, and 24 transudate pleural effusion patients, respectively. Chemokines (CCL2, CCL7, and CX3CL1) and cytokines (IL-1β, IL-17, IL-27, and IFN-γ) were measured by ELISA. The monocytes phenotypes were analyzed by flow cytometry. The chemokines receptors (CCR2 and CX3CR1) and cytokines above in different monocytes subsets were analyzed by real-time PCR. Receiver operating characteristic curve analysis was performed for displaying differentiating power of intermediate and nonclassical subsets between tuberculous and malignant pleural effusions.CCL7 and CX3CL1 levels in TPE were significantly elevated in TPE compared with MPE and transudate pleural effusion. Cytokines, such as IL-1β, IL-17, IL-27, and IFN-γ, in TPE were much higher than in other pleural effusions. Moreover, CD14CD14 and CD16 markers on monocytes could be potentially used as novel diagnostic markers for diagnosing TPE and MPE.

Summary Background Use of an interferon-γ (IFN-γ) release assay or tuberculin skin test for detection and management of latent tuberculosis infection is controversial. For both types of test, we assessed their predictive value for the progression of latent infection to active tuberculosis disease, the targeting value of preventive treatment, and the necessity of dual testing. Methods In this systematic review and meta-analysis, we searched PubMed, Embase, Web of Science, and the Cochrane Library, with no start date or language restrictions, on Oct 18, 2019, using the keywords (“latent tuberculosis” OR “latent tuberculosis infection” OR “LTBI”) AND (“interferon gamma release assays” OR “Interferon-gamma Release Test” OR “IGRA” OR “QuantiFERON®-TB in tube” OR “QFT” OR “T-SPOT.TB”) AND (“tuberculin skin test” OR “tuberculin test” OR “Mantoux test” OR “TST”). We included articles that used a cohort study design; included information that individuals with latent tuberculosis infection detected by IFN-γ release assay, tuberculin skin test, or both, progressed to active tuberculosis; reported information about treatment; and were limited to high-risk populations. We excluded studies that included patients with active or suspected tuberculosis at baseline, evaluated a non-commercial IFN-γ release assay, and had follow-up of less than 1 year. We extracted study details (study design, population investigated, tests used, follow-up period) and the number of individuals observed at baseline, who progressed to active tuberculosis, and who were treated. We then calculated the pooled risk ratio (RR) for disease progression, positive predictive value (PPV), and negative predictive value (NPV) of IFN-γ release assay versus tuberculin skin test. Findings We identified 1823 potentially eligible studies after exclusion of duplicates, of which 256 were eligible for full-text screening. From this screening, 40 studies (50 592 individuals in 41 cohorts) were identified as eligible and included in our meta-analysis. Pooled RR for the rate of disease progression in untreated individuals who were positive by IFN-γ release assay versus those were negative was 9·35 (95% CI 6·48–13·49) compared with 4·24 (3·30–5·46) for tuberculin skin test. Pooled PPV for IFN-γ release assay was 4·5% (95% CI 3·3–5·8) compared with 2·3% (1·5–3·1) for tuberculin skin test. Pooled NPV for IFN-γ release assay was 99·7% (99·5–99·8) compared with 99·3% (99·0–99·5) for tuberculin skin test. Pooled RR for rates of disease progression in individuals positive by IFN-γ release assay who were untreated versus those who were treated was 3·09 (95% CI 2·08–4·60) compared with 1·11 (0·69–1·79) for the same populations who were positive by tuberculin skin test. Pooled proportion of disease progression for individuals who were positive by IFN-γ release assay and tuberculin skin test was 6·1 (95% CI 2·3–11·5). Pooled RR for rates of disease progression in individuals who were positive by IFN-γ release assay and tuberculin skin test who were untreated versus those who were treated was 7·84 (95% CI 4·44–13·83). Interpretation IFN-γ release assays have a better predictive ability than tuberculin skin tests. Individuals who are positive by IFN-γ release assay might benefit from preventive treatment, but those who are positive by tuberculin skin test probably will not. Dual testing might improve detection, but further confirmation is needed. Funding National Natural Science Foundation of China and Natural Foundation of Yunnan Province.

Lyme disease (LD) is an infectious disease caused by the spirochetes of genus borrelia, which are transmitted by the ticks of the genus ixodes. LD is transmitted by the spirochete B. burgdorferi sensu lato. Once in contact with the host through a tick bite, the pathogen comes into contact with the host defense, and must escape this machinery to establish LD, thus using a large number of mechanisms involving the vector of the pathogen, the pathogen itself and also the host. The initial diagnosis of the disease can be made based on the clinical symptoms of LD and the disease can be treated and cured with antibiotics if the diagnosis is made early in the beginning of the disease. Contrariwise, if LD is left untreated, the pathogen disseminates throughout the tissues and organs of the body, where it establishes different types of disease manifestations. In the nervous system, the inflammation caused by B. burgdorferi is known as Lyme neuroborreliosis (LNB). LNB is one of the principal manifestations of LD. In this review, we systematically describe the different molecular interactions among B. burgdorferi, the vector (tick) and the mammalian host.

Background Clinical research has frequently not been taught in a practical way, often resulting in a very didactic approach rendering it not very accessible for medical undergraduates. Simulation can provide an immersive, interactive, and reflective experience and may be applied to the clinical research curriculum. Methods A 7-step model, modified from Kern’s six-step approach and Khamis’s stepwise model, was used to develop the curriculum. A questionnaire survey on undergraduates’ attitude towards, knowledge and practice of clinical research and simulation education was conducted to generate a targeted needs assessment. The simulation framework was integrated into the development of educational strategies. Experts were consulted to assess the curriculum prior to implementation. Results Talent construction in China needs an innovative capability-enhanced clinical research curriculum. Sixty-six clinical undergraduates in our school completed the survey. 89.39% (59/66) of them hadn’t participated in clinical research, while 93.94% (62/66) would like to conduct clinical trials if possible. 75.76% of respondents didn’t have knowledge of or practical abilities in clinical trials. The mean score for practical ability (2.02 ± 0.92) was lower than that of knowledge (2.20 ± 0.93) (P P = 0.04) and learning for themselves (P Conclusions The targeted needs assessment exposed medical undergraduates’ poor knowledge of and abilities in clinical research. This is the first report of a simulation-based clinical research curriculum developed in China, and adds curriculum development and design details to the limited related published studies.

Monocytes are involved in tumor growth and metastasis, but the distribution of monocyte phenotypes and their role in the development of malignant pleural effusion (MPE) remains unknown.A total of 94 MPE patients (76 diagnosed with adenocarcinoma lung cancer and 18 with squamous cell lung cancer) and 102 volunteers for health examination in Xiangya Hospital from December 2016 to December 2019 were included in the study.The distribution of monocyte subtypes identified by the expression of CD14 and CD16 were analyzed by flow cytometry. The proportion of CD14C5a, activated by the classical and alternative pathways of the complement system, not only mediated the infiltration of intermediate monocytes by enhancing CCL2 production in PMCs but also induced IL-1β release from the recruited monocytes in MPE. The consequence of C5a activation and the subsequent IL-1β overexpression in intermediate monocytes contributed to MPE progression.

Background Lyme disease is a zoonotic disease caused by infection with Borrelia burgdorferi (Bb), the involvement of the nervous system in Lyme disease is usually referred to as Lyme neuroborreliosis (LNB). LNB has diverse clinical manifestations, most commonly including meningitis, Bell’s palsy, and encephalitis. However, the molecular pathogenesis of neuroborreliosis is still poorly understood. Comprehensive transcriptomic analysis following Bb infection could provide new insights into the pathogenesis of LNB and may identify novel biomarkers or therapeutic targets for LNB diagnosis and treatment. Methods In the present study, we pooled transcriptomic datasets (transcriptomic rhesus data from our laboratory and the GSE85143 dataset from the Gene Expression Omnibus database) to screen common differentially expressed genes (DEGs) in the Bb infection group and the control group. Functional and enrichment analyses were conducted using the Database of Annotation Visualization and Integrated Discovery database, Protein-Protein Interaction network, and hub genes were identified using the Search Tool for the Retrieval of Interaction Genes database and the CytoHubba plugin. In addition, in vitro and ex vivo assays were performed to verify the above findings. The mRNA expression levels of these genes were verified by quantitative real-time PCR (qPCR). Results A total of 80 upregulated DEGs and 32 downregulated DEGs were identified. Among them, 11 hub genes were selected. Upregulated genes in the Gene Ontology analysis were significantly enriched in cell adhesion processes. The pathway enrichment analyses revealed that the PI3K-Akt signaling pathway was significantly enriched. The mRNA levels of ANGPT1, TLR6, SREBF1, LDLR, TNC, and ITGA2 in U251 cells and/or rhesus brain explants by exposure to Bb were validated by qPCR. Conclusion Our study suggested that TLR6, ANGPT1, LDLR, SREBF1, TNC, and ITGA were differentially highly expressed in Bb-infected astrocytes compared to normal controls, and overexpression of LDLR might be a favorable prognostic factor of LNB patients. Further study is needed to explore the value of TLR6, ANGPT1, LDLR, SREBF1, TNC, and ITGA in LNB pathogenesis.

In the present study, we sought to elucidate the mechanisms by which monocytes migrate into the pleural space in the presence of anaphylatoxins in tuberculous pleural effusion (TPE). Monocytes in both pleural effusion and blood were counted, and their phenotypic characteristics were analyzed. Activation of the complement system was detected in TPE. The effects of Mpt64 and anaphylatoxins on the production of chemokines in pleural mesothelial cells (PMCs) were measured. The chemoattractant activity of chemokines produced by PMCs for monocytes was observed. Levels of CD14+CD16+ monocytes were significantly higher in TPE than in blood. Three pathways of the complement system were activated in TPE. C3a-C3aR1, C5a-C5aR1, CCL2-CCR2, CCL7-CCR2, and CX3CL1-CX3CR1 were coexpressed in PMCs and monocytes isolated from TPE. Moreover, we initially found that Mpt64 stimulated the expression of C3a and C5a in PMCs. C3a and C5a not only induced CCL2, CCL7, and CX3CL1 expression in PMCs but also stimulated production of IL-1β, IL-17, and IL-27 in monocytes. C3a and C5a stimulated PMCs to secrete CCL2, CCL7, and CX3CL1, which recruited CD14+CD16+ monocytes to the pleural cavity. As a result, the infiltration of CD14+CD16+ monocytes engaged in the pathogenesis of TPE by excessive production of inflammatory cytokines.

Bisphenol A molecular imprinted adsorbent (BMIA) was successfully synthesized by a sol-gel process and showed a good specific binding performance in the water. The further studies showed that the mass transfer process was controlled by in-diffusion, and the synthesis conditions would effect on the amount of imprinting sites. Scatchard model analysis evidenced that the high binding affinity sites and the low binding affinity sites were both on BMIA, and the high binding affinity sites played a key role in the specific binding process. Scatchard model analysis of temperature effect experiments and dosage effect experiments proved that the specific binding sites with high binding affinity and the unexpressed specific binding sites with low binding affinity were the two different states of the imprinting binding sites. The conversion between the two different states depended on the reaction driving force, and the increasing reaction driving force would increase the number of specific binding sites. Especially, the temperature showed a linear positive correlation with the amount of specific binding sites. Finally, a possible model was put forward to explain the two different states conversion mechanism of the imprinting sites.

Background: Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis. Until now, molecular mechanisms underlying the occurrence, development and prognosis of tuberculosis have not been fully characterized. The aim of the study was to identify hub genes involved in tuberculosis.Methods: We used four microarray datasets (GSE51029, GSE52819, GSE54992, and GSE65517) from the Gene Expression Omnibus (GEO) and GEO2R software to identify differentially expressed genes (DEGs) between samples from humans infected with M. tuberculosis and a healthy control group (using cutoffs of LogFC > 1 and p value < 0.05). DEGs shared by the four microarray datasets were further identified. Next, we carried out functional enrichment analysis using the Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG); Then, the host hub genes with a relatively high number of connections to other DEGs, were identified by Cytoscape. Other bioinformatics methods are also performed, including protein–protein interaction (PPI) network analysis and construction of miRNA–hub gene networks and transcription factors (TF)–hub gene networks. Finally, the expression of the host hub genes was verified using the reverse transcription polymerase chain reaction(RT–PCR).Results: A total of 46 DEGs were identified. GO analysis showed that the biological functions of DEGs were mainly in immune response regulation, cytokine/chemokine activity, and receptor ligand activity. DEGs were significantly enriched in membrane rafts, the mitochondrial outer membrane, cytoplasmic vesicle cavities, and nuclear chromatin. KEGG enrichment analysis showed involvement of the genes in the NOD-like receptor and toll-like receptor signaling pathways. Five highly differentially expressed hub genes – STAT1, TLR7, CXCL8, CCR2, and CCL20 – were identified. Finally, based on NetworkAnalyst's database, we constructed miRNA–hub gene networks and TF–hub gene networks.Conclusions: In summary, bioinformatics analyses were used to identify DEGs to find potential biomarkers that may be associated with tuberculosis. This study provides a set of candidate DEGs and five important hub genes that can be potential for the early detection, prognostic determination, risk assessment, and targeted therapy of tuberculosis.

Background Lyme neuroborreliosis (LNB) is one of the most dangerous manifestations of Lyme disease, but the pathogenesis and inflammatory mechanisms are not fully understood. Methods Cultured explants from the frontal cortex of rhesus monkey brain (n=3) were treated with live Borrelia burgdorferi (Bb) or phosphate-buffered saline (PBS) for 6, 12, and 24 h. Total protein was collected for sequencing and bioinformatics analysis. In addition, changes in protein expression in the explants over time following Bb treatment were screened. Results We identified 1237 differentially expressed proteins (DEPs; fold change ≥1.5 or ≤0.67, P-value ≤0.05). One of these, growth-associated protein 43 (GAP-43), was highly expressed at all time points in the explants. The results of the protein-protein interaction network analysis of DEPs suggested that GAP-43 plays a role in the neuroinflammation associated with LNB. In HMC3 cells incubated with live Bb or PBS for 6, 12, and 24 h, real-time PCR and western blot analyses confirmed the increase of GAP-43 mRNA and protein, respectively. Conclusions Elevated GAP-43 expression is a potential marker for LNB that may be useful for diagnosis or treatment.

Background: Allergic bronchopulmonary aspergillus (ABPA) is a complex non-infectious pulmonary benign disease caused by immune response against to aspergillus. Carcinoembryonic antigen (CEA) is a tumor marker but also elevated in some benign diseases. Few studies on ABPA with elevated serum CEA levels have been reported. Objects: This study aims to comb the clinical characters of ABPA with elevated serum CEA. Methods: 20 patients diagnosed as ABPA were divided into two groups (CEA normal and CEA elevated) for retrospective analysis. The eosinophil count and ratio, IgE level in the pretherapy and post-treatment were compared. Serum samples of patients with ABPA (n = 20) and asthma (n = 20), healthy controls (n=20) were collected. Levels of cytokines (IL-4, IL-5, GM-CSF, IFN-γ) were analyzed by enzyme-linked immunosorbent assay. Results: We found that in ABPA patients with normal serum CEA levels, eosinophil counts and IgE levels decreased more obviously after treatment. Besides, we established higher serum levels of IL-4, IL-5, GM-CSF and IFN-γ in ABPA patients with elevated serum CEA levels.Conclusion: For the ABPA patients with elevated serum CEA levels, CEA may serve as a monitoring indicator for severity and treatment efficacy of ABPA.

BackgroundUrinary tract infections (UTIs) are some of the most common infections worldwide and consume a lot of medical resources every year. However, there were a lack of available data on its incidence and disease burden. We armed to investigate incidence, mortality, and disability adjusted life-years (DALYs) of urinary tract infections (UTIs) from 1990 to 2017.MethodsWe extracted data from the Global Burden of Disease Study 2017, then calculated estimated annual percentage changes (EAPC) of age-standardized incidence rate (ASIR), age-standardized death rate (ASDR), and age-standardized DALYs rate at global, national, regional, and socio-demographic index (SDI) level.ResultsFrom 1990 to 2017, the globally incident cases (+52.09%), death cases (+140.10%), and DALYs (+69.65%) of UTIs all increased. The ASIR, ASDR, and age-standardized DALYs rate showed upward trends with the EAPC of +0.10 (95%CI: 0.07 to 0.12), +0.72 (95%CI: 0.65-0.78), and +0.06 (95%CI: -0.05 to 0.16), respectively. The ASIR decreased only in the high-middle SDI quantile (-0.26, 95%CI: -0.3 to -0.23). United Arab Emirates had the largest increase of DALYs (+835.04%), but Bulgaria had the largest decrease (-80.74%). EAPC for incidence and mortality were below 0 mainly in Europe and East Asia. In 2017, the incident cases (+3.44 times), the deaths (+1.31 times), and DALYs (+1.21 times) were all higher in females than males. The incident cases were mainly concentrated in 15-49 years old; DALYs and mortality were higher in over 80 age groups.Conclusions Globally, the burden of UTIs increased from 1990 to 2017, especially in females; however, distinct varies were observed in different regions and countries. The infants and elders are easier to die when they suffer from UTIs.

The complement system is activated in tuberculous pleural effusion (TPE), with increased levels of the anaphylatoxins stimulating pleural mesothelial cells (PMCs) to secrete chemokines, which recruit nonclassical monocytes to the pleural cavity. The differentiation and recruitment of naive CD4+ T cells are induced by pleural cytokines and PMC-produced chemokines in TPE. However, it is unclear whether anaphylatoxins orchestrate CD4+ T cell response via interactions between PMCs and monocytes in TPE. In this study, CD16+ and CD16- monocytes isolated from TPE patients were cocultured with PMCs pretreated with anaphylatoxins. After removing the PMCs, the conditioned monocytes were cocultured with CD4+ T cells. The levels of the cytokines were measured in PMCs and monocyte subsets treated separately with anaphylatoxins. The costimulatory molecules were assessed in conditioned monocyte subsets. Furthermore, CD4+ T cell response was evaluated in different coculture systems. The results indicated that anaphylatoxins induced PMCs and CD16+ monocytes to secrete abundant cytokines capable of only inducing Th17 expansion, but Th1 was feeble. In addition, costimulatory molecules were more highly expressed in CD16+ than in CD16− monocytes isolated from TPE. The interactions between monocytes and PMCs enhanced the ability of PMCs and monocytes to produce cytokines and that of monocytes to express HLA-DR, CD40, CD80 and CD86, which synergistically induced Th17 expansion. In the above process, anaphylatoxins enhanced the interactions between monocytes and PMCs by increasing the level of the cytokines IL-1β, IL-6, IL-23 and upregulating the phenotype of CD40 and CD80 in CD16+ monocytes. Collectively, these data indicate that anaphylatoxins play a central role in orchestrating Th17 response mainly via interactions between CD16+ monocytes and PMCs in TPE., Author summary Tuberculous pleural effusion is characterized by intense chronic accumulations of fluid and lymphocyte cells and monocytes/macrophages in the pleural space. Complement mediators play important roles in providing protection against Mycobacterium tuberculosis. Our results demonstrated that Mycobacterium tuberculosis infection induced the amplification of complement activation in TPE. Complement activation produces anaphylatoxins that induce PMCs and CD16+ monocytes to secrete abundant cytokines capable of only inducing Th17 expansion, but Th1 was feeble. In addition, costimulatory molecules were more highly expressed in CD16+ than in CD16− monocytes isolated from TPE. The interactions between monocytes and PMCs enhanced the ability of PMCs and monocytes to produce cytokines and that of monocytes to express HLA-DR, CD40, CD80 and CD86, which synergistically induced Th17 expansion. In the above process, anaphylatoxins enhanced the interactions between monocytes and PMCs by increasing the level of the cytokines IL-1β, IL-6, IL-23 and upregulating the phenotype of CD40 and CD80 in CD16+ monocytes. In summary, these data highlighted the importance of anaphylatoxins and the innate immune system in eliciting pathogenic T cell responses in TPE and suggested that monocytes, especially the CD16+ subset, might be an efficient target for controlling inflammation.

Organoids are derived from stem cells or organ-specific progenitors. They display structures and functions consistent with organs in vivo. Multiple types of organoids, including lung organoids, can be generated. Organoids are applied widely in development, disease modelling, regenerative medicine, and other multiple aspects. Various human pulmonary diseases caused by several factors can be induced and lead to different degrees of lung epithelial injury. Epithelial repair involves the participation of multiple cells and signalling pathways. Lung organoids provide an excellent platform to model injury to and repair of lungs. Here, we review the recent methods of cultivating lung organoids, applications of lung organoids in epithelial repair after injury, and understanding the mechanisms of epithelial repair investigated using lung organoids. By using lung organoids, we can discover the regulatory mechanisms related to the repair of lung epithelia. This strategy could provide new insights for more effective management of lung diseases and the development of new drugs.

Stroke is the first leading cause of death in China, and low fruit intake is suggested to be one of the most important risk factors for stroke mortality. However, the trends of stroke mortality attributable to low fruit intake remain unclear in China. Therefore, this study aimed to investigate the long-term trends of stroke mortality attributable to low fruit intake by sex in China during 1990–2017. Data were obtained from the Global Burden of Disease 2017 study; the annual percentage change (APC) and average annual percentage change (AAPC) were estimated by joinpoint regression analysis, and the net age, period, and cohort effects were estimated using the age–period–cohort model with an intrinsic estimator algorithm (APC-IE). The crude mortality rates (CMRs) increased for males and decreased for females from 1990 to 2017. The age-standardized mortality rates (ASMRs) for both males and females showed consecutive significant declines from 1990 to 2017. By APC analysis, substantially increasing age effects were presented from 25 to 79 years for both sexes. The independent period and cohort effects progressively decreased during the entire period for both sexes, with a faster decrease for females than for males. Males and elder groups were the high-risk population for stroke mortality caused by low fruit intake. Although the mortality risk showed a decreasing trend, the fruit intake was still low for the Chinese population. Therefore, effective strategies and global awareness are essential to improve the current situation of low fruit intake, thereby preventing and reducing the stroke mortality risk caused by low fruit intake in China.

Certain natural products, derived from medicinal plants, exhibit anti-inflammatory properties, but the mechanism of action of many remains unclear. Borrelia burgdorferi spirochetes are responsible for causing Lyme arthritis through activation of the Toll-like receptor (TLR) signaling pathway. In this study, we investigated the mechanisms by which Isoforskolin (ISOF) and Cucurbitacin IIa (CuIIa), compounds derived from Chinese herbs, can exert anti-inflammatory effects by modulating single immunoglobulin interleukin-1 receptor-related receptor (SIGIRR; also known as Toll/interleukin-1 receptor 8, TIR8) and thereby inhibiting B. burgdorferi basic membrane protein A (BmpA)-induced TLR signaling in human macrophages, specifically the THP-1 human monocytic cell line. After THP-1 cells were exposed in vitro to: i) recombinant (r)BmpA, ii) rBmpA and ISOF or iii) rBmpA and CuIIa, Cytotoxicity assay (Cell Counting Kit-8, CCK-8) are used to measure the effects of ISOF and CuIIa on cell viability. Meanwhile, real-time polymerase chain reaction and Western blotting were used to quantify SIGIRR mRNA and protein levels, respectively, at 6, 12, 24 and 48 h time points post-stimulation. In addition, proinflammatory cytokine tumor necrosis factor-α (TNF-α) was determined by ELISA analysis. Our study showed that rBmpA stimulation of THP-1 cells resulted in a drop in SIGIRR levels in THP-1 cells. More importantly, SIGIRR levels increased significantly in rBmpA-stimulated THP-1 cells following ISOF or CuIIa administration, and the results of ELISA analysis suggested that ISOF or CuIIa reduced the secretion of the proinflammatory cytokine TNF-α. In conclusion, These results reveal new possibilities for the treatment of Lyme arthritis.

The tick-borne pathogen Anaplasma phagocytophilum is an emerging infectious disease threat, but the overall A. phagocytophilum seroprevalence in humans is unclear. We performed a systematic search of English databases for literature published from 1994 to 2018. Studies reporting serological evidence of A. phagocytophilum infection in humans were included, and the information was extracted by two authors independently. As the study heterogeneity was significant, a random-effects model was used to calculate the overall pooled seroprevalence. Data from 56 studies involving 28,927 individuals from four continents were included. The seroprevalence reported by the studies ranged from 0% to 37.26%. The overall pooled A. phagocytophilum seroprevalence in humans was 8.4% (95% CI: 6.6%-10.4%). The seroprevalence was highest in high-risk population (13.8%) and lowest in healthy population (5.0%). The estimated A. phagocytophilum seroprevalence of febrile patient, tick-bitten and tick-borne diseases populations was 6.4%, 8.0% and 9.0%, respectively. This meta-analysis demonstrated first A. phagocytophilum seroprevalence estimates in different populations (healthy, febrile patient, high-risk, tick-bitten and tick-borne diseases populations); it seems likely that present surveillance efforts are missing mild or asymptomatic infections of humans.

Objectives: We hope to identify key molecules that can be used as markers of asthma severity and investigate their correlation with immune cell infiltration in severe asthma. Methods: An asthma dataset was downloaded from the Gene Expression Omnibus database and then processed by R software to obtain differentially expressed genes (DEGs). First, multiple enrichment platforms were applied to analyze crucial biological processes and pathways and protein–protein interaction networks related to the DEGs. We next combined least absolute shrinkage and selection operator logistic regression and the support vector machine-recursive feature elimination algorithms to screen diagnostic markers of severe asthma. Then, a local cohort consisting of 40 asthmatic subjects (24 with moderate asthma and 16 with severe asthma) was used for biomarker validation. Finally, infiltration of immune cells in asthma bronchoalveolar lavage fluid and their correlation with the screened markers was evaluated by CIBERSORT. Results: A total of 97 DEGs were identified in this study. Most of these genes are enriched in T cell activation and immune response in the asthma biological process. CC-chemokine receptor 7 (CCR7) and natural killer cell protein 7(NKG7) were identified as markers of severe asthma. The highest area under the ROC curve (AUC) was from a new indicator combining CCR7 and NKG7 (AUC = 0.851, adj. p < 0.05). Resting and activated memory CD4 T cells, activated NK cells, and CD8 T cells were found to be significantly higher in the severe asthma group (adj. p < 0.01). CCR7 and NKG7 were significantly correlated with these infiltrated cells that showed differences between the two groups. In addition, CCR7 was found to be significantly positively correlated with eosinophils (r = 0.38, adj. p < 0.05) infiltrated in bronchoalveolar lavage fluid. Conclusion: CCR7 and NKG7 might be used as potential markers for asthma severity, and their expression may be associated with differences in immune cell infiltration in the moderate and severe asthma groups.

Rotavirus immunization strategies have become part of a comprehensive global public health program to control rotavirus-associated gastroenteritis, particularly in infants and children in developing countries. Several studies have reported the efficacy of different rotavirus vaccine dosing schedules, but with mixed findings. Therefore a systematic review of the published literature on rotavirus vaccination dosing schedules using the live attenuated RV1 rotavirus vaccine in infants and children, including randomized controlled clinical trials (RCTs), published between January 1998 to January 2018 was conducted, with meta-analysis of the published data. The literature search was performed using six databases. The initial review identified 495 publications, of which three satisfied the selection eligibility criteria. The three studies that assessed RV1 rotavirus vaccine immunogenicity compared a two-dose vaccination schedule with a three-dose vaccination schedule. The use of a three-dose vaccination schedule did not show a statistically significant seroconversion rate when compared with a two-dose vaccination schedule (OR = 0.87; 95% CI,: 0.65--1.17;, p- = 0.298). Analysis of included studies with one-month follow-up time showed that the three-dose vaccination schedule did not result in have significantly increased geometric mean concentrations (GMCs) compared with the two-dose vaccination schedule (p = 0.311).Rotavirus immunogenicity did not increase significantly with the three-dose schedule at 6, 10 and 14 weeks with the two-dose schedule at 10 and 14 weeks. These findings indicate that further controlled studies should be undertaken to support the optimum immunization schedules for rotavirus in terms of clinical effectiveness and cost-effectiveness, particularly for infants and children in developing countries.

Tetracycline hydrochloride (TCH) degradation by cobalt modified silicate ore (CoSO) catalytic ozonation in aqueous solution was investigated. CoSO catalyst was synthesized by an impregnation method using Co(NO3)2 as the precursor and natural silicon ore (SO) as the support. The key catalyst preparation conditions (i.e., impregnation concentration, calcination temperature and time) were optimized. The activity and stability of CoSO catalyst and its catalytic ozonation mechanism for TCH degradation were studied. The results showed that Co3O4 was successfully coated on the silicon ore and the CoSO catalyst was highly efficient in catalytic ozonation for TCH degradation. The TCH removal by CoSO/O3 could reach 93.2%, while only 69.3% by SO/O3 and only 46.0% by O3 alone at 25 min. The reaction of TCH degradation followed pseudo-first order kinetics. TOC removal rate by CoSO/O3 was 2.0 times higher than that by SO/O3, and 3.5 times higher than that by O3 alone. The reaction conditions (TCH initial concentration, catalyst concentration, pH and temperature) for catalytic ozonation were systematically investigated. The possible mechanism for the CoSO catalytic ozonation process was proposed, where hydroxyl radical oxidation mainly accounted for the substantial TCH degradation. Furthermore, CoSO showed great durability and stability after seven reaction cycles.

Manganese modified silicate ore (MnSO) prepared using an impregnation method was used as a heterogeneous ozonation catalyst, and the catalytic activity was evaluated by the degradation of ciprofloxacin (CIP). The results showed that the manganese oxide was successfully loaded onto natural silicate ore (SO). The degradation and mineralization efficiencies of CIP were considerably improved in the presence of MnSO. Under optimal conditions, the CIP removal process followed the pseudo-first-order reaction model well. The degradation rate constant of MnSO/O3 was 1.7 times and 3.3 times higher than those of SO/O3 and only O3, respectively. During the ozonation of the CIP aqueous solution in the presence of MnSO, the TOC removal rate reached 61.2% at 60 min, but was only 30.8% using ozonation alone. The addition of tert-butanol (TBA) significantly inhibited the degradation efficiency of CIP, which indicated that catalytic ozonation of MnSO followed a hydroxyl radical (·OH) reaction mechanism. Furthermore, MnSO showed great stability and durability over several reaction cycles.

Assembling colloidal particle under oscillatory electric field (OEF) has become an emerging bottom-up technique to synthesize advanced materials and fabricate micro/nano devices. Surfactants have been often used in colloid dispersions for improving their stability. However, the precise roles of surfactants in particle assembly processes under OEF are unknown. Here, we systematically study the effects of ionic surfactants on the colloidal particle assembling process subject to a fixed OEF, by using an anionic surfactant (sodium dodecyl sulfate, SDS) and a cationic surfactant (cetyltrimethylammonium bromide, CTAB). In the concentration range below the critical micelle concentration (CMC), the particles tend to form three different aggregate structures, including randomly close-packed (RCP), hexagonally closed-packed (HCP) crystal, and randomly nonclose-packed (RNCP) structures. In the concentration range at CMC and above, the particles cannot assemble into any aggregate structures under the given OEF. With increasing the surfactant concentration, the average interparticle separation distance within the aggregate can be regulated in a wide range. We qualitatively interpret the observed variation of particle assembling behaviors in different surfactant solutions based on the particle/particle interaction energy, implying that the repulsive EDL interaction is significantly enhanced with increasing the ionic surfactant concentration and hinders the particles approaching close with high energy barrier. These results suggest that the particle aggregate structures and interparticle separation distance of the 2D colloidal assembly can be manipulated by controlling the ionic surfactant concentration according to the requirements of practical applications.

Borrelia burgdorferi (Bb), which is neurotropic, can attack the central nervous system (CNS), leading to the development of various neurologic symptoms. The pathogenesis of Lyme neuroborreliosis (LNB) remains poorly understood. Presently, there is a lack of knowledge of the changes in mRNA and proteins in the CNS following early disseminated Lyme disease. Explants from the frontal cortex of 3 rhesus brains were incubated with medium alone or with medium containing live Bb for 6, 12, or 24 hours. Then, we analyzed identified mRNA and proteins in the frontal cortex tissues, allowing for an in-depth view of the transcriptome and proteome for a macroscopic and unbiased understanding of early disseminated Lyme disease in the brain. Through bioinformatics analysis, a complex network of enriched pathways that were mobilized during the progression of Lyme spirochete infection was described. Furthermore, based on the analysis of omics data, translational regulation, glycosaminoglycan/proteoglycan-binding activity in colonization and dissemination to tissues, disease-associated genes, and synaptic function were enriched, which potentially play a role in pathogenesis during the interaction between frontal cortex tissues and spirochetes. These integrated omics results provide unbiased and comprehensive information for the further understanding of the molecular mechanisms of LNB.

Background: Although immune cells, such as mast cell, is suggested to play a critical role in the pathogenesis of malignant pleural effusion (MPE), the role and underlying mechanism of non-classical in MPE has yet to be fully elucidated. Objectives: To compare the distribution and phenotype of monocytes in MPE with transudate pleural effusion. To elucidate the possible role of inflammatory cytokines in non-classical monocytes in the pathogenesis of MPE. Methods: Monocytes and its phenotype in both pleural effusion and blood was counted by flow cytometry. The express level of chemokines receptors and inflammatory cytokines in non-classical monocytes was detected by PCR and ELISA. The role of IL-1βin the proliferation, apoptosis, invasion, adhesion and EMT of A549 cells was measured by WB, flow cytometry, and wound healing test. Measurements and Main Results: Human non-classical monocyte compartment was increased in MPE, compared to transudate pleural effusion patients. MPE expressed high level of chemokines (CCL2 and CX3CL1) and cytokines IL-1β. Non-classical monocytes isolated from MPE expressed high levels of CCR2, CX3CR1 and IL-1βcompared to classical monocytes. Recruitment of non-classical monocytes into MPE regulated by PMCs could suffer as a result of anti-CCL2 and anti-CX3CL1 mAbs. IL-1βpromote the pathogenesis of MPE by inducing the proliferation, immigration, invasion, and EMT, and inhibiting the apoptosis and adhesion of A549 cells, while utilizing IL-1RA weaken these effects. Conclusions: Non-classical monocytes accumulates in the pleural cavity and promote the formation of MPE by secretion abundant IL-1β.

CD4+ T cells are involved in the pathogenesis of immunoglobulin A nephropathy (IgAN); T helper (Th) 1, Th17 and Th22 cells promote the occurrence and amplification of inflammatory reactions, while regulatory T (Treg) cells produce the opposite effects. However, whether Th9 cells, a subset of CD4+ T cells, participate in IgAN development is still unknown. Human peripheral blood mononuclear cells (PBMCs) were isolated from IgAN patients for Th9 cells detection by flow cytometry. Wild-type (WT) mouse was used to establish an IgAN mouse model while C3aR and C5aR inhibitor treated IgAN mouse. Kidney disease and function was assessed by histology and albumin-to-creatinine ratio. C3aR and C5aR expression was examined by immunohistochemical (IHC) assay. Th9 cell proportions in the blood of IgAN mouse was detected. C3a, C5a and interleukin (IL)-9 levels were tested by ELISA. Moreover, co-culture system between human mesangial cells (HMCs) and CD4+ T cells were constructed with or without C3a, C5a and anti-CCL20 mAb stimulation for transwell assay to examine Th9 cell chemotaxis. We observed the numbers of Th9 cell and the levels of IL-9 were increased in IgAN patients and IgAN mice. Furthermore, C3a and C5a level in serum and kidney, C3aR and C5aR expression was increased in IgAN mice compared to WT mice. Most interestingly, C3aR and C5aR inhibitor could reduce kidney damage, Th9 cell numbers and IL-9 levels. We also observed that C3a and C5a enhanced CCL20 production in HMCs. Notably, C3a and C5a also increased the recruitment of Th9 cells and IL-9 levels by HMCs through enhancing the CCL20-CCR6 pathway. Our results support that C3a and C5a increase the production of CCL20 by HMCs and consequently augment Th9 cell recruitment and IL-9 levels, resulting in IgAN exacerbation.

Background: Currently, there is no tuberculosis (TB) vaccine recommended for use in latent TB infections and healthy adults. M72/AS01E is a new peptide vaccine currently under development, which may improve protection against TB disease. This vaccine has been investigated in several phase I/II clinical trials. We conducted a meta-analysis to clarify the immunogenicity and safety of the M72/AS01E peptide vaccine. Methods: We searched the PubMed, Embase, and Cochrane Library databases for published studies (until December 2018) investigating this candidate vaccine. A meta-analysis was performed using the standard methods and procedures established by the Cochrane Collaboration. Results: Seven eligible studies—involving 4,590 participants—were selected. The analysis revealed a vaccine efficacy was 57.0%, significantly higher abundance of polyfunctional M72-specific CD4+ T cells [standardized mean difference (SMD) = 2.58] in the vaccine group vs. the control group, the highest seropositivity rate [relative risk (RR) = 74.87] at 1 month after the second dose of vaccination (Day 60), and sustained elevated anti-M72 IgG geometric mean concentration at study end (Day 210) (SWD = 4.94). Compared with the control, participants who received vaccination were at increased risk of local injection site redness [relative risk (RR) = 5.99], local swelling (RR = 7.57), malaise (RR = 3.01), and fatigue (RR = 3.17). However, they were not at increased risk of headache (RR = 1.57), myalgia (RR = 0.97), and pain (RR = 3.02). Conclusion: The M72/AS01E vaccine against TB is safe and effective. Although the vaccine is associated with a mild adverse reaction, it is promising for the prevention of TB in healthy adults.

Lyme neuroborreliosis (LNB) is the most dangerous manifestation of Lyme disease caused by the spirochete Borrelia burgdorferi which can reach the central nervous system most commonly presenting with lymphocytic meningitis; however, the molecular basis for neuroborreliosis is still poorly understood. We incubated explants from the frontal cortex of three rhesus brains with medium alone or medium with added live Borrelia burgdorferi for 6, 12, and 24 h and isolated RNA from each group was used for RNA sequencing with further bioinformatic analysis. Transcriptomic differences between the ex vivo model of live Borrelia burgdorferi with rhesus frontal cortex tissue explants and the controls during the progression of the infection were identified. A total of 2249, 1064, and 420 genes were significantly altered, of which 80.7, 52.9, and 19.8% were upregulated and 19.3, 47.1, 80.2% were downregulated at 6, 12, and 24 h, respectively. Gene ontology and KEGG pathway analyses revealed various pathways related to immune and inflammatory responses during the spirochete infection were enriched which is suggested to have a causal role in the pathogenesis of neurological Lyme disease. Moreover, we propose that the overexpressed FOLR2 which was demonstrated by the real-time PCR and western blotting could play a key role in neuroinflammation of the neuroborreliosis based on PPI analysis for the first time. To our knowledge, this is the first study to provide comprehensive information regarding the transcriptomic signatures that occur in the frontal cortex of the brain upon exposure to Borrelia burgdorferi, and suggest that FOLR2 is a promising target that is associated with neuroinflammation and may represent a new diagnostic or therapeutic marker in LNB.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) which has been threatening global public health for many years. High genetic diversity is dominant feature of Mtb. Increasing cases of multidrug-resistant (MDR) tuberculosis (MDR-TB) is a serious public health problem to TB control in China. Spontaneous mutations in the Mtb genome can alter proteins which are the target of drugs, making the bacteria drug resistant. The purpose of the present study was to analyze the genotype of Mtb isolates from some areas in Yunnan, China and explore the association between genotypes and MDR-TB. Using spoligotyping, we identified Beijing genotypes, six non-Beijing genotypes and a number of orphan genotypes from 270 Mtb isolates from patients in Yunnan Province during 2014–2016. Of 270 Mtb isolates, 102 clinical Mtb strains were identified as drug-resistant (DR) by drug susceptibility testing (DST), among them, 52 MDR strains. Beijing genotypes occupied the highest MDR proportion (78.85%) followed by the orphan genotypes (15.38%). The characteristics of MDR strains showed high genetic diversity. The results will help to efficiently improve diagnosis and treatment and provide valuable information for Mtb molecular epidemiology.

Cytokines play a crucial role in mediating immune responses to tuberculosis (TB). The aim of this study was to evaluate the levels of cytokines in patients with different forms of pulmonary tuberculosis (PTB) and identify valuable cytokine biomarkers for the diagnosis of PTB. We measured the levels of six cytokines (interleukin (IL-2, IL-4, IL-6, and IL-10), tumor necrosis factor (TNF-α), and interferon-γ (IFN-γ)) in the serum of healthy donors (n = 30). Patients with active PTB (n = 46) and those with latent tuberculosis infection (LTBI, n = 38) were examined using cytometric bead arrays. The levels of the six cytokines in the serum samples were measured promptly, sensitively, and simultaneously. The levels of IL-2, IL-6, IL-10, and IFN-γ were significantly higher in the PTB group compared with those reported in the healthy donors ( P

Lyme neuroborreliosis (LNB) is the most dangerous manifestation of Lyme disease caused by the spirochete Borrelia burgdorferi which can reach the central nervous system most commonly presenting with lymphocytic meningitis; however, the molecular basis for neuroborreliosis is still poorly understood. We incubated explants from the frontal cortex of three rhesus brains with medium alone or medium with added live Borrelia burgdorferi for 6, 12, and 24 h and isolated RNA from each group was used for RNA sequencing with further bioinformatic analysis. Transcriptomic differences between the ex vivo model of live Borrelia burgdorferi with rhesus frontal cortex tissue explants and the controls during the progression of the infection were identified. A total of 2249, 1064, and 420 genes were significantly altered, of which 80.7, 52.9, and 19.8% were upregulated and 19.3, 47.1, 80.2% were downregulated at 6, 12, and 24 h, respectively. Gene ontology and KEGG pathway analyses revealed various pathways related to immune and inflammatory responses during the spirochete infection were enriched which is suggested to have a causal role in the pathogenesis of neurological Lyme disease. Moreover, we propose that the overexpressed FOLR2 which was demonstrated by the real-time PCR and western blotting could play a key role in neuroinflammation of the neuroborreliosis based on PPI analysis for the first time. To our knowledge, this is the first study to provide comprehensive information regarding the transcriptomic signatures that occur in the frontal cortex of the brain upon exposure to Borrelia burgdorferi, and suggest that FOLR2 is a promising target that is associated with neuroinflammation and may represent a new diagnostic or therapeutic marker in LNB.

Background: There are controversies regarding the use of the interferon-γ release assay (IGRA) or tuberculin skin test (TST) for the detection of latent tuberculosis infection (LTBI). We assessed three factors relevant to the detection of LTBI: predictive value of progression to active TB, target value of preventive treatment, and the necessity of combination of IGRA and TST. Methods: We searched PubMed, EMBASE, Web of Science, and the Cochrane Library for relevant studies until April 2019. We calculated the risk ratio (RR) for the rates of disease progression in persons with positive versus negative test to assess the predictive value. We calculated the positive predictive value (PPV) and RR for the rates of disease progression in untreated versus treated persons of the positive test to assess the target value of preventive treatment. We calculated the proportion of disease progression in the combination groups and RR for rates of disease progression in untreated versus treated persons to assess the necessity of combination. Findings: A total of 31 relevant studies including 46775 persons were included in the final analysis. The strength of the association between IGRA+ results, as well as TST+, and development of active TB was high. However, IGRA+ was higher than TST+. The PPV of IGRA+ persons was higher than TST+, and the PPV of QuantiFERON®-TB (QFT) was the highest. The association between untreated and development with QFT+ was strong, unlike that of other single tests. The proportion of progressed IGRA+/TST+ persons was the highest in the combination tests. Moreover, the proportion of progressed persons in the IGRA+/TST− group was significantly higher than that observed in the IGRA−/TST+ and IGRA−/TST− groups. The association between untreated and development with IGRA+/TST+ group was stronger than that of any other single use group. Interpretation: Both IGRA and TST can predict the subsequent development of active TB; however, IGRA is more reliable than TST. IGRA is more accurate for targeting preventive treatment and offers more benefit from treatment than TST. Furthermore, QFT is a optimal recommendation for single use, and the combination of IGRA and TST is unnecessary. Funding Statement: National Natural Science Foundation of China (grant numbers 81860644, 81560596, and 31560051), and Natural Foundation of Yunnan Province (grant numbers 2017FE467-001 and 2014FA011). Declaration of Interests: The authors declare no potential conflicts of interest.

Background: Currently, there is no tuberculosis (TB) vaccine recommended for use in latent TB infections and healthy adults. M72/AS01E is a new peptide vaccine currently under development, which may improve protection against TB disease. This vaccine has been investigated in several phase I/II clinical trials. We conducted a meta-analysis to clarify the immunogenicity and safety of the M72/AS01E peptide vaccine. Methods: We searched the PubMed, Embase, and Cochrane Library databases for published studies (until December 2018) investigating this candidate vaccine. A meta-analysis was performed using the standard methods and procedures established by the Cochrane Collaboration. Findings: Seven eligible studies - involving 4,590 participants - were selected. The analysis revealed a vaccine immunogenicity of 58.90%, significantly higher abundance of M72-specific CD4+ T cells (standardized mean difference [SMD]=2.58) in the vaccine group versus the control group, the highest seropositivity rate (74.87%) at 1 month after the second dose of vaccination (Day 60), and sustained elevated anti-M72 IgG geometric mean concentration at study end (Day 210) (SWD=4.94). Compared with the control, participants who received vaccination were at increased risk of local injection site redness (relative risk [RR]=5.99), local swelling (RR=7.57), malaise (RR=3.01), and fatigue (RR=3.17). However, they were not at increased risk of headache (RR=1.57), myalgia (RR=0.97), and pain (RR=3.02). Interpretation: The M72/AS01E vaccine against TB is safe and effective. Although the vaccine is associated with a mild adverse reaction, it is promising for the prevention of TB in healthy adults. Funding: National Natural Science Foundation of China, Scientific and Technological Development Project of Yunnan Province of China. Declaration of Interest: The authors declare no competing interests.

High heterogeneity has been reported among epidemiological studies exploring the relationship between metformin and the risk of gastric cancer. Immortal time bias might be one of the vital factors causing heterogeneity because of its widespread existence in pharmacological observational studies and it could severely exaggerate the drug's effectiveness. Immortal time bias could occur in an observational study if exposure status is determined based on a measurement or event that occurs after baseline. In this study, we aimed to assess whether immortal time bias is responsible for the false assumption that metformin reduces the risk of gastric cancer. We searched PubMed, Embase, Web of Science and Cochrane Library databases for relevant studies from the inception to August 9, 2020. The strength of the relationship was assessed using pooled relative risks (RRs) with corresponding 95% confidence intervals (95% CIs). Statistical analyses were carried out using a random-effects model. Pooled RR from 6 cohort studies with immortal time bias found a clear 33% reduced risk associated with metformin use (RR = 0.67, 95% CI = 0.59, 0.77; P < 0.001; I2 = 48.5%). However, pooled RR from 8 cohort studies without immortal time bias indicated no association between the use of metformin and gastric cancer risk (RR = 0.95, 95% CI = 0.85, 1.05; P = 0.317; I2 = 64.5%). From a univariate meta-regression model, the presence of immortal time bias was associated with a significant reduction of 29% in the effect estimate of metformin on gastric cancer risk (ratio of RR = 0.71, 95% CI = 0.58, 0.86; P = 0.002). This meta-analysis indicates that metformin use has no protective effect on gastric cancer risk. The relationship between metformin use and gastric cancer risk has been exaggerated as a result of the presence of immortal time bias. Further studies are required to confirm the results by controlling for immortal time bias based on appropriate study designs and statistical methods.

The layer rate optimization of a video layered multicast, in heterogeneous network, includes the number of layers, layer rate, and bandwidth of the user links. In order to solve the NP-hard problem in layer rate optimization, a Layer Rate Allocation Optimization with User Cluster (UC-LRAO) algorithm is proposed. The number of users in each layer and the corresponding user bandwidth carrying video streaming is obtained according to the total user number. Then the video streaming link bandwidth of users of each layer is allocated by introducing the Edmonds-Karp Max-flow Min-cut algorithm and intra-layer network coding. Finally, according to the expected layer number of the layered video streaming, the video streaming is layered again and reconstructed by clustering the users. Then, the layer rate and link bandwidth are optimized and allocated. Simulation results show that the proposed algorithm can improve the system throughput.

In cellular network, users with same demand and in proximity to each other form the mobile cloud, in which the short-range D2D technology is employed by users to improve the data dissemination efficiency. In view of the fact that the D2D links with the poor channel conditions are likely to be the bottleneck of resource utilization improvement, aiming at the differentiation of link quality, this paper proposes a intra-cloud D2D multicast retransmission algorithm based on SINR constraint to meet the minimum requirement of D2D retransmission for QoS. In the proposed algorithm, the model of system link cost is built, the number of multicast retransmission times is restricted and each link quality matrix is traversed to reasonably select the multicast transmitter as well as its routing, which further reduces the link cost consumption, and in turn improves the bandwidth efficiency. Simulation results show that the proposed algorithm is more efficient to improve the bandwidth utilization when the ratio between normal user and non-normal user is small in mobile cloud.

Key Points Question Which antibiotic is associated with the greatest efficacy and safety for treating scrub typhus? Findings In this network meta-analysis of 14 studies, 8 antibiotics that are the most commonly used for treating scrub typhus showed no significant advantage or disadvantage with regard to efficacy or safety. In retrospective studies, clarithromycin alleviated fever more efficiently than other antibiotics. Meaning The findings of analysis for efficacy, safety, and defervescence time of these 8 antibiotics may provide a reference for clinical decision-making., Importance Antibiotics have been used for many years to treat scrub typhus, but their efficacy and safety have not been studied thoroughly. Objective To compare and rank different antibiotics to identify which one can safely eliminate Orientia tsutsugamushi and efficiently alleviate fever in patients with scrub typhus. Data Sources An electronic search of PubMed and Embase was conducted, from database inception to July 12, 2019. The study was conducted from July 12 to September 2, 2019. Study Selection Randomized clinical trials and retrospective studies that evaluated the use of antibiotics for treatment in patients diagnosed with scrub typhus caused by O tsutsugamushi were included. Records of articles in English were considered eligible. Studies were assessed independently by 2 reviewers, with disagreement resolved by consensus. Of 6408 studies initially identified, 10 randomized clinical trials and 4 retrospective study met the criteria for further analysis. Data Extraction and Synthesis This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension statement for systematic reviews incorporating network meta-analyses of health care interventions. Data were independently extracted by 2 reviewers and synthesized with frequentist random-effects network meta-analyses. Main Outcomes and Measures The primary outcome was efficacy of the antibiotic, considered as the number of patients who achieved complete healing with an antibiotic. Safety, defined as the prevalence of adverse events associated with the antibiotics, was the secondary outcome, and defervescence time was the tertiary outcome. P scores (scale of 0 to 1, with 1 indicating superiority to other treatments) were used to rank the efficacy, safety, and defeverescence time of the antibiotics. Results Three searches for articles in Embase and PubMed identified 10 randomized clinical trials (888 participants) and 4 retrospective studies (323 participants) for further analyses. No particular treatment regimen showed a significant advantage or disadvantage with regard to efficacy or safety. However, meta-analysis of retrospective studies indicated that clarithromycin (P score = 0.8730) alleviated fever more efficiently than other antibiotics. Conclusions and Relevance No treatment regimen reported in this network meta-analysis showed a significant advantage or disadvantage with regard to efficacy or safety. However, clarithromycin might be a better choice than the other drugs for alleviating fever., This network meta-analysis compares the efficacy and safety of 8 antibiotics used for treatment of scrub typhus.

Tetracycline hydrochloride (TCH) degradation by cobalt modified silicate ore (CoSO) catalytic ozonation in aqueous solution was investigated. CoSO catalyst was synthesized by an impregnation method using Co(NO