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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.

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.

Lyme disease (LD) is a heavy public health burden. The most common manifestations of LD include erythema migrans (EM), Lyme neuroborreliosis (LNB), and Lyme arthritis (LA). The efficacy and safety of antibiotics for treating LD is still controversial. Thus, we performed a network meta-analysis (NMA) to obtain more data and tried to solve this problem. We searched studies in the databases of Embase and PubMed from the date of their establishments until 22 April 2021. Odds ratios (ORs) were used to assess dichotomous outcomes. A total of 31 randomized controlled trials (RCTs) involving 2,748 patients and 11 antibiotics were included. Oral amoxicillin (1.5 g/day), oral azithromycin (0.5 g/day), injectable ceftriaxone, and injectable cefotaxime were effective for treating LD (range of ORs, 1.02 to 1,610.43). Cefuroxime and penicillin were safe for treating LD (range of ORs, 0.027 to 0.98). Amoxicillin was effective for treating EM (range of ORs, 1.18 to 25.66). Based on the results, we thought oral amoxicillin (1.5 g/day), oral azithromycin (0.5 g/day), injectable ceftriaxone, and injectable cefotaxime were effective for treating LD. Cefuroxime and penicillin were safe for treating LD. Amoxicillin was effective for treating EM. We did not observe evidence proving the advantage of doxycycline in efficacy and safety for treating LD, LA, LNB, and EM of children or adults. We did not have sufficient data to prove the significant difference of efficacy for treating LA and LNB in adults and LD in children, the significant difference of safety of oral drugs for treating LD, and the significant difference of safety of drugs for treating EM. IMPORTANCE Some previous studies investigated the efficacy and safety of antibiotics for treating Lyme disease (LD). However, due to technical limitations, several questions regarding the routes of drug administration and the dosages of drug are still unclear, which might be causing problems for clinicians. Hence, we performed network meta-analysis (NMA) to quantitatively analyze the clinical data published during the last 40 years. Here, we demonstrate the evidence regarding the efficacy and safety of antibiotics commonly used for treating LD in adults and children. We found that amoxicillin, azithromycin, ceftriaxone, and cefotaxime were effective for treating LD, but we did not observe significant efficacy and safety of doxycycline for treating LD.

GLCCI1 plays a significant role in modulating glucocorticoid (GC) sensitivity in asthma. This project determines the underlying mechanism that GLCCI1 deficiency attenuates GC sensitivity in dexamethasone (Dex)-treated Ovalbumin (OVA)-induced asthma mice and epithelial cells through upregulating binding of IRF1:GRIP1 and IRF3:GRIP1. Dexamethasone treatment led to less reduced inflammation, airway hyperresponsiveness, and activation of the components responsible for GC activity, as determined by decreased GR and glucocorticoid receptor interacting protein 1 (GRIP1) expression but augmented IRF1 and IRF3 expression in GLCCI1−/− asthmatic mice compared with wild type asthmatic mice. Moreover, the recruitment of GRIP1 to GR was downregulated, while the individual recruitment of GRIP1 to IRF1 and IRF3 was upregulated in GLCCI1−/− Dex-treated asthmatic mice compared to wild type Dex-treated asthmatic mice. We also found that GLCCI1 knockdown reduced GR and GRIP1 expression but increased IRF1 and IRF3 expression in Beas2B and A549 cells. Additionally, GLCCI1 silencing increased the interactions between GRIP1 with IRF1 and GRIP1 with IRF3, but decreased the recruitment of GRIP1 to GR. These studies support a critical but previously unrecognized effect of GLCCI1 expression on epithelial cells in asthma GC responses by which GLCCI1 deficiency reduces the GR and GRIP1 interaction but competitively enhances the recruitment of GRIP1 to IRF1 and IRF3.

BackgroundLyme neuroborreliosis (LNB) is one of the most dangerous manifestations of Lyme disease, but the pathogenesis and inflammatory mechanisms are not fully understood.MethodsCultured 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.ResultsWe 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.ConclusionsElevated GAP-43 expression is a potential marker for LNB that may be useful for diagnosis or treatment.

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.

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.

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.

Background The novel coronavirus disease (COVID-19) was first reported in Wuhan, China. The mass population mobility in China during the Spring Festival has been considered a driver to the transmission of COVID-19, but it still needs more empirical discussion. Methods Based on the panel data from Hubei, China between January 6th and February 6th, 2020, a random effects model was used to estimate the impact of population mobility on the transmission of COVID-19. Stata version 12.0 was used, and p Results The COVID-19 was more likely to be confirmed within 11–12 days after people moved from Wuhan to 16 other prefecture-level cities in Hubei Province, which suggests a period of 11–12 days from contact to being confirmed. The daily confirmed cases and daily increment in incidence in 16 prefecture-level cities show obvious declines 9–12 days post adaptation of city lockdown at the local level. Conclusion Population mobility is found to be a driver to the rapid transmission of COVID-19, and the lockdown intervention in local prefecture-level cities of Hubei Province has been an effective strategy to block the COVID-19 epidemic.

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.

Ixodes ticks are the main vectors for a number of zoonotic diseases, including Lyme disease. Ticks secrete saliva directly into a mammalian host while feeding on the host's blood. This action serves to modulate host immunity and coagulation, thus allowing ticks to attach and feed upon their host. One of the most extensively studied components of tick saliva is Salp15. Research has shown that this protein binds specifically to CD4 molecules on the surface of T lymphocytes, interferes with TCR-mediated signaling transduction, inhibits CD4+ T cell activation and proliferation, and impedes the secretion of interleukin 2 (IL-2). Salp15 also binds specifically to dendritic cell dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) to up-regulate the expression of CD73 in regulatory T cells. Collectively, these findings render this salivary protein a potential candidate for a range of therapeutic applications. Here, we discuss our current understanding of Salp15 and the mechanisms that might be used to treat disease.

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.

Background Ischaemic heart disease (IHD) is a major barrier to sustainable human development, but its health burden and geographic distribution among provinces of China remain unclear. This study aimed to estimate IHD burden in provinces of China, and attributable to risk factors from 1990 to 2015. Methods Data were collected from the Global Burden of Disease 2015 Study, which evaluated IHD burden and attributable risk factors using deaths and disability-adjusted life years (DALYs). Statistical models including cause of death ensemble modelling, Bayesian meta-regression analysis, and comparative risk assessment approaches were applied to reduce bias and produce comprehensive results of IHD deaths, DALYs and attributable risks. The 95% uncertainty intervals (UIs) were calculated and reported for mortality and DALYs. Results The age-standardised death rate per 100,000 people increased by 13.3% from 101.3 (95%UI: 95.3–107.5) to 114.8 (95%UI: 109.8–120.1) from 1990 to 2015 in China, whereas the age-standardised DALY rate declined 3.9% to 1760.2 per 100,000 people (95%UI: 1671.6–1864.3). In 2015, the age-standardised death rate per 100,000 people was the highest in Heilongjiang (187.4, 95%UI: 161.6–217.5) and the lowest in Shanghai (44.2, 95%UI: 37.0–53.1), and the age-standardised DALY rate per 100,000 people was the highest in Xinjiang (3040.8, 95%UI: 2488.8–3735.4) and the lowest in Shanghai (524.4, 95%UI: 434.7–638.4). Geographically, the age-standardised death and DALY rates for southern provinces were lower than northern provinces, especially in southeastern coastal provinces. 95.3% of the IHD burden in China was attributable to environmental, behavioural and metabolic risk factors. The five leading IHD risks in 2015 were high systolic blood pressure, high total cholesterol, diet high in sodium, diet low in whole grains, and smoking. Conclusions Population growth and ageing has led to a steady increase in the IHD burden. Regional disparities in IHD burden were observed in provinces of China. The distribution characteristics of IHD burden provide guidance for decision makers to formulate targeted preventive policies and interventions. Electronic supplementary material The online version of this article (10.1186/s12872-018-0761-0) contains supplementary material, which is available to authorized users.

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 disease, reffered to as Lyme borreliosis, is a tick-borne zoonotic disease caused by Borrelia burgdorferi spirochetes. Lyme arthritis, the most common, serious and harmful manifestation during the late stages of Lyme disease, is closely associated with the Borrelia burgdorferi basic membrane protein A (BmpA). Chemokines are also reported to have an important role in Lyme arthritis. Toll-like receptors (TLRs) recognize and bind to pathogen-associated molecules which are structurally conserved among microbes, to activate transcriptional events, including cytokine production, inflammation, and tissue damage. We speculated that BmpA could induce a storm of proinflammatory chemokines via TLRs and downstream moleculars, and that TLR1, TLR2, TLR5, TLR6 and the adaptor protein, MyD88, may be involved in this process. We explored this hypothesis using the human monocytic leukemia cell line, THP-1, and recombinant BmpA (rBmpA). Cell surface TLR1 and TLR2 were neutralized using specific antibodies before stimulation with rBmpA and analysis of chemokine secretion using a chemokine chip. Further, the expressions level of the four TLRs and MyD88 were analyzed following stimulation with rBmpA. Stimulation with rBmpA resulted in elevated levels of seven cytokines. Further, TLR1 and TLR2 antibody treated cells exhibited an overall reduction in rBmpA-induced chemokine expression. TLR1, TLR2, and MyD88 expression levels (both mRNA and protein) increased after stimulation with rBmpA. Our data confirm that TLR1, TLR2, and MyD88 are involved in BmpA-induced proinflammatory chemokines, which may be closely involved in Lyme arthritis pathogenesis.

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.

Respiratory viral infections can directly lead to kidney damage such as IgA nephropathy (IgAN), partly due to mucosal immune system dysfunction. Although the activated C5a-C5aR1 axis results in increased Th1 and Th17 frequencies but reduced Treg frequencies in Respiratory syncytial virus (RSV) infection, how this axis affects Th cell disorders in RSV-induced IgAN exacerbation remains unknown. Here, we used a mouse model to dissect the activation of C5a-C5aR1 by RSV and the consequences on the regulation of Th1, Th17, and Treg immune responses in IgA nephropathy. RSV fusion protein was clearly deposited not only in the pulmonary interstitium but also in the glomerulus in RSV-IgAN mice, and RSV infection led to more severe pathological changes in the kidneys in IgAN mice. Blocking the C5a-C5aR1 axis resulted in a decrease in the albumin-to-creatinine ratio, and the attenuation of kidney damage in IgAN and RSV-IgAN mice might be partly attributed to the inhibition of Th cell and cytokine dysfunction. Th1, Th17 and Treg immune responses and their corelative cytokines were disrupted by RSV infection and rescued by C5aR1 inhibition. Moreover, we constructed a coculture system of human mesangial cells and CD4+ T cells and found that RSV infection might lead to CD4+ T cell production via human mesangial cells-enhanced CD4+ T cell proliferation, consequently increasing IL-17 levels. These pathological behaviors were augmented by C5a stimulation and decreased by C5aR1 inhibition. Thus, C5aR1 inhibition alters both kidney damage and Th1, Th17, and Treg cell dysfunction in RSV-induced IgAN exacerbation and locally regulates HMC antigen presentation function in the kidney. Taken together, our data offer profound evidence that blocking the C5a-C5aR1 axis might be a potential therapy for RSV-induced IgAN.

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

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.

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.

An amendment to this paper has been published and can be accessed via the original article.

In this study, we estimated the short-term effects of ambient air pollution on respiratory disease hospitalization in Taiyuan, China. Daily data of respiratory disease hospitalization, daily concentration of ambient air pollutants and meteorological factors from 1 October 2014 to 30 September 2017 in Taiyuan were included in our study. We conducted a time-series study design and applied a generalized additive model to evaluate the association between every 10-&mu, g/m3 increment of air pollutants and percent increase of respiratory disease hospitalization. A total of 127,565 respiratory disease hospitalization cases were included in this study during the present period. In single-pollutant models, the effect values in multi-day lags were greater than those in single-day lags. PM2.5 at lag02 days, SO2 at lag03 days, PM10 and NO2 at lag05 days were observed to be strongly and significantly associated with respiratory disease hospitalization. No significant association was found between O3 and respiratory disease hospitalization. SO2 and NO2 were still significantly associated with hospitalization after adjusting for PM2.5 or PM10 into two-pollutant models. Females and younger population for respiratory disease were more vulnerable to air pollution than males and older groups. Therefore, some effective measures should be taken to strengthen the management of the ambient air pollutants, especially SO2 and NO2, and to enhance the protection of the high-risk population from air pollutants, thereby reducing the burden of respiratory disease caused by ambient air pollution.

We analyzed the temporal and spatial variations in mortality burden of cirrhosis and liver cancer attributable to injection drug use (IDU) from 1990 to 2016. Mortality data of IDU-attributable cirrhosis and IDU-attributable liver cancer on the global and national scales from 1990 to 2016 were collected from the Global Burden of Disease (GBD) studies. Age-period-cohort (APC) model analysis was used to analyze the global mortality trends of target disease, and spatial autocorrelation analysis based on Geographic Information System was applied to illustrate the clusters of the most epidemic countries. Globally, from 1990 to 2015, mortality rates (age-standardized, per 100,000) of IDU-attributable cirrhosis increased continually from 1.5 to 1.9, while from 0.4 to 0.9 for IDU-attributable liver cancer. The APC model analysis indicated that the increases of mortality were mainly driven by period effects, with the mortality risk increasing by 6.82-fold for IDU-attributable cirrhosis and 3.08-fold for IDU-attributable liver cancer. The spatial analysis suggested that IDU-attributable cirrhosis mortality were geographically clustered from 1990 to 2016, and hot spots were mainly located in less well developed countries of Latin America, East and Central Europe and Central Asia. Our study provides epidemiological evidence for global interventions against advanced liver disease among injection drug users (IDUs).

Asthma exacerbation could be induced by respiratory syncytial virus (RSV), and the underlying pathogenic mechanism is related to complement activation. Although complement might regulate CD4+T cells immune responses in asthma model, this regulation existed in RSV-induced asthma model remains incompletely characterrized. In this study, we assessed the contribution of C5a-C5aR to CD4+T cell immune responses in RSV-infected asthma mice. Female BALB/C mice were sensitized and challenged with ovalbumin (OVA) while treated with RSV infection and C5a receptor antagonist (C5aRA) during challenge period. RSV enhanced lung damage, airway hyperresponsiveness, and C5aR expressions in asthma mice, while C5aRA alleviated these pathologic changes. The percentages of Th1, Th2 and Th17 cells were increased, while the percentage of Treg cells was decreased in RSV-infected asthma mice compared with asthma mice. IFN-γ, IL-4, IL-10 and IL-17A levels have similar trend with Th1, Th2, Th17 and Treg cells. Notably, above changes of CD4+T cells and their related cytokines were reversed by C5aRA. Together, the data indicates that RSV infection could apparently increase C5a and C5aR expression in the pathogenesis of RSV-infected asthma mice, meanwhile C5aRA prevents some of the CD4+T cells immune changes that are induced by RSV.

In this study, we analyzed the temporal and spatial variations of stroke mortality attributable to ambient particulate matter pollution (stroke mortality-PM2.5) in China from 1990 to 2015. Data were collected from the Global Burden of Disease (GBD) 2015 study and analyzed by an age-period-cohort model (APC) with an intrinsic estimator (IE) algorithm, as well as spatial autocorrelation based on the Geographic Information System. Based on APC analysis with the IE method, stroke mortality-PM2.5 increased exponentially with age, its relative risk reaching 42.85 (95% CI: 28.79, 63.43) in the 75–79 age group. The period effects showed a reversed V-shape and its highest relative risk was 1.22 (95% CI: 1.15, 1.27) in 2005. The cohort effects decreased monotonically from 1915–1919 to 1990–1994. The change rate fluctuated from 1920–1924 to 1990–1994, including three accelerating and three decelerating decreases. There was a positive spatial autocorrelation in stroke mortality-PM2.5 from 1990 to 2015. Hot-spots moved from the northeastern areas to the middle and southwestern areas, whereas cold-spots lay mostly in coastal provinces. Besides the aging process in recent years, stroke mortality-PM2.5 had significantly declined from 2005 to 2015 due to socio-economic and healthcare development. Stroke mortality-PM2.5 varied substantially among different regions, and cost-effective prevention and control should be implemented more in the middle and southwestern areas of China.

Background and Purpose— Stroke has been the leading cause of death in China. The aim of this study is to assess the long-term trends of stroke mortality in China between 1994 and 2013. Methods— The mortality data were obtained from the GBD 2013 (Global Burden of Disease Study 2013) and were analyzed with the age–period–cohort framework. Results— We found that the net drift was −2.665% (95% confidence interval, −2.854% to −2.474%) per year for men and −4.064% (95% confidence interval, −4.279% to −3.849%) per year for women, and the local drift values were below 0 in all age groups ( P P P Conclusions— The decreased mortality rates of stroke in China are likely to be related to improvements in medical care and techniques, spectacular economic growth and fast urbanization, and better early life nutrition conditions of Chinese people. Besides, better education and better awareness of stroke-related knowledge in successive generations could also probably play a role.

The aim of this study was to provide data on the dose dependence of manganese-enhanced MRI (MEMRI) in the visual pathway of experimental rats and to study the toxicity of MnCl₂ to the retina. Sprague-Dawley rats were intravitreally injected with 2 μL of 0, 10, 25, 50, 75, 100, 150 and 300 mM MnCl₂, respectively. The contrast-to-noise ratio (CNR) of MEMRI for optic nerve enhancement was measured at different concentrations of MnCl₂. Simultaneously, the toxicity of manganese was evaluated by counting retinal ganglion cells and by retinal histological examination using light microscopy and transmission electron microscopy. The CNR increased with increasing concentration of MnCl₂ up to 75 mM. Retinal ganglion cell densities were reduced significantly when the concentration of MnCl₂ in the intravitreal injection was equal to or greater than 75 mM. Increasing numbers of ribosomes in retinal ganglion cells were first detected at 25 mM of MnCl₂. The retinal toxicity of MnCl₂ at higher concentration also included mitochondrial pathology and cell disruption of retinal ganglion cells, as well as abnormalities of photoreceptor and retinal pigment epithelium cells. It can be concluded that intravitreal injection of MnCl₂ induces retinal cell damage that appears to start from 25 mM. The concentration of MnCl₂ should not exceed 25 mm through intravitreal injection for visual pathway MEMRI in the rat.

This study aimed to identify and compare the mortality trends for road injuries in China and the United States, and evaluate the contributions of age, period, and cohort effects to the trends from 1990 to 2014. Using the 2016 Global Burden of Disease Study database, the mortality trends were analyzed by joinpoint regression and age-period-cohort modeling. Overall, the mortality for road injuries was higher in China than in the United States. The mortality in China increased from 1992 to 2002 (annual percent change [APC] was 1.9%), and then decreased from 2002 to 2015 (APC2002&ndash, 2009 was 1.5%, APC2009&ndash, 2015 was 3.5%). For the United States, the mortality decreased from 1990 to 2010 (APC1990&ndash, 1997 was 1.8%, APC1997&ndash, 2005 was 0.7%, APC2005&ndash, 2010 was 4.2%). Age-period-cohort modeling revealed significant period and cohort effects. Compared with the period 2002&ndash, 2004, the period risk ratios (RRs) in 2010&ndash, 2014 period declined by 14.62% for China and 18.86% for the United States. Compared with the 1955&ndash, 1959 birth cohort, the cohort RRs for China and the United States in the 2010&ndash, 2014 cohort reduced by 47.60% and 75.94%, respectively. Period and cohort effects could not be ignored for reducing road injury mortalities.