Establishment of human cerebral organoid systems to model early neural development and assess the central neurotoxicity of environmental toxins.

JOURNAL/nrgr/04.03/01300535-202501000-00032/figure1/v/2024-05-14T021156Z/r/image-tiff Human brain development is a complex process, and animal models often have significant limitations. To address this, researchers have developed pluripotent stem cell-derived three-dimensional structures, known as brain-like organoids, to more accurately model early human brain development and disease. To enable more consistent and intuitive reproduction of early brain development, in this study, we incorporated forebrain organoid culture technology into the traditional unguided method of brain organoid culture. This involved embedding organoids in matrigel for only 7 days during the rapid expansion phase of the neural epithelium and then removing them from the matrigel for further cultivation, resulting in a new type of human brain organoid system. This cerebral organoid system replicated the temporospatial characteristics of early human brain development, including neuroepithelium derivation, neural progenitor cell production and maintenance, neuron differentiation and migration, and cortical layer patterning and formation, providing more consistent and reproducible organoids for developmental modeling and toxicology testing. As a proof of concept, we applied the heavy metal cadmium to this newly improved organoid system to test whether it could be used to evaluate the neurotoxicity of environmental toxins. Brain organoids exposed to cadmium for 7 or 14 days manifested severe damage and abnormalities in their neurodevelopmental patterns, including bursts of cortical cell death and premature differentiation. Cadmium exposure caused progressive depletion of neural progenitor cells and loss of organoid integrity, accompanied by compensatory cell proliferation at ectopic locations. The convenience, flexibility, and controllability of this newly developed organoid platform make it a powerful and affordable alternative to animal models for use in neurodevelopmental, neurological, and neurotoxicological studies.

Picroside â ¡ attenuates neuropathic pain by regulating inflammation and spinal excitatory synaptic transmission.

Nerve injury induced microglia activation, which released inflammatory mediators and developed neuropathic pain. Picroside Ⅱ (PⅡ) attenuated neuropathic pain by inhibiting the neuroinflammation of the spinal dorsal horn; however, how it engaged in the cross talk between microglia and neurons remained ambiguous. This study aimed to investigate PⅡ in the modulation of spinal synaptic transmission mechanisms on pain hypersensitivity in neuropathic rats. We investigated the analgesia of PⅡ in mechanical and thermal hyperalgesia using the spinal nerve ligation (SNL)-induced neuropathic pain model and formalin-induced tonic pain model, respectively. RNA sequencing and network pharmacology were employed to screen core targets and signaling pathways. Immunofluorescence staining and qPCR were performed to explore the expression level of microglia and inflammatory mediator mRNA. The whole-cell patch-clamp recordings were utilized to record miniature excitatory postsynaptic currents in excitatory synaptic transmission. Our results demonstrated that the analgesic of PⅡ was significant in both pain models, and the underlying mechanism may involve inflammatory signaling pathways. PⅡ reversed the SNL-induced overexpression of microglia and inflammatory factors. Moreover, PⅡ dose dependently inhibited excessive glutamate transmission. Thus, this study suggested that PⅡ attenuated neuropathic pain by inhibiting excitatory glutamate transmission of spinal synapses, induced by an inflammatory response on microglia.

Modeling early human cortical development and evaluating neurotoxicity with a forebrain organoid system.

The complexity and subtlety of brain development renders it challenging to examine effects of environmental toxicants on human fetal brain development. Advances in pluripotent cell-derived organoid systems open up novel avenues for human development, disease and toxicity modeling. Here, we have established a forebrain organoid system and recapitulated early human cortical development spatiotemporally including neuroepithelium induction, apical-basal axis formation, neural progenitor proliferation and maintenance, neuronal differentiation and layer/region patterning. To explore whether this forebrain organoid system is suitable for neurotoxicity modeling, we subjected the organoids to bisphenol A (BPA), a common environmental toxicant of global presence and high epidemic significance. BPA exposure caused substantial abnormalities in key cortical developmental events, inhibited progenitor cell proliferation and promoted precocious neuronal differentiation, leading premature progenitor cell depletion and aberrant cortical layer patterning and structural organization. Consistent with an antagonistic mechanism between thyroid hormone and BPA, T3 supplementation attenuated BPA-mediated cortical developmental abnormalities. Altogether, our in vitro recapitulation of cortical development with forebrain organoids provides a paradigm for efficient neural development and toxicity modeling and related remedy testing/screening.

Glioma stem cells and neural stem cells respond differently to BMP4 signaling.

Malignant glioma is a highly heterogeneous and invasive primary brain tumor characterized by high recurrence rates, resistance to combined therapy, and dismal prognosis. Glioma stem cells (GSCs) are likely responsible for tumor progression, resistance to therapy, recurrence, and poor prognosis owing to their high self-renewal and tumorigenic potential. As a family member of BMP signaling, bone morphogenetic protein4 (BMP4) has been reported to induce the differentiation of GSCs and neural stem cells (NSCs). However, the molecular mechanisms underlying the BMP4-mediated effects in these two cell types are unclear. In this study, we treated hGSCs and hNSCs with BMP4 and compared the phenotypic and transcriptional changes between these two cell types. Phenotypically, we found that the growth of hGSCs was greatly inhibited by BMP4, but the same treatment only increased the cell size of hNSCs. While the RNA sequencing results showed that BMP4 treatment evoked significantly transcriptional changes in both hGSCs and hNSCs, the profiles of differentially expressed genes were distinct between the two groups. A gene set that specifically targeted the proliferation and differentiation of hGSCs but not hNSCs was enriched and then validated in hGSC culture. Our results suggested that hGSCs and hNSCs responded differently to BMP4 stimulation. Understanding and investigating different responses between hGSCs and hNSCs will benefit finding partner factors working together with BMP4 to further suppress GSCs proliferation and stemness without disturbing NSCs.

Interferon-beta inhibits human glioma stem cell growth by modulating immune response and cell cycle related signaling pathways.

Malignant Glioma is characterized by strong self-renewal potential and immature differentiation potential. The main reason is that malignant glioma holds key cluster cells, glioma stem cells (GSCs). GSCs contribute to tumorigenesis, tumor progression, recurrence, and treatment resistance. Interferon-beta (IFN-ß) is well known for its anti-proliferative efficacy in diverse cancers. IFN-ß also displayed potent antitumor effects in malignant glioma. IFN-ß affect both GSCs and Neural stem cells (NSCs) in the treatment of gliomas. However, the functional comparison, similar or different effects of IFN-ß on GSCs and NSCs are rarely reported. Here, we studied the similarities and differences of the responses to IFN-ß between human GSCs and normal NSCs. We found that IFN-ß preferentially inhibited GSCs over NSCs. The cell body and nucleus size of GSCs increased after IFN-ß treatment, and the genomic analysis revealed the enrichment of the upregulated immune response, cell adhesion genes and down regulated cell cycle, ribosome pathways. Several typical cyclin genes, including cyclin A2 (CCNA2), cyclin B1 (CCNB1), cyclin B2 (CCNB2), and cyclin D1 (CCND1), were significantly downregulated in GSCs after IFN-ß stimulation. We also found that continuous IFN-ß stimulation after passage further enhanced the inhibitory effect. Our study revealed how genetic diversity resulted in differential effects in response to IFN-ß treatment. These results may contribute to improve the applications of IFN-ß in anti-cancer immunotherapy. In addition, these results may also help to design more effective pharmacological strategies to target cancer stem cells while protecting normal neural stem cells.

Tuberculosis treatment management in primary healthcare sectors: a mixed-methods study investigating delivery status and barriers from organisational and patient perspectives.

OBJECTIVE: Tuberculosis (TB) treatment management services (TTMSs) are crucial for improving patient treatment adherence. Under the TB integrated control model in China, healthcare workers (HCWs) in the primary healthcare (PHC) sectors are responsible for TTMS delivery. This mixed-method study aimed to explore the status of and barriers to TTMS delivery faced by HCWs in PHC sectors from the health organisational and patient perspectives. DESIGN: We completed a questionnaire survey of 261 TB healthcare workers (TB HCWs) and 459 patients with TB in the PHC sector and conducted 20 semistructured interviews with health organisational leaders, TB HCWs and patients with TB. SPSS V.22.0 and the framework approach were used for data analysis. SETTING: PHC sectors in Southwest China. RESULTS: Our results showed that TTMS delivery rate by HCWs in PHC sectors was <90% (88.4%) on average, and the delivery rates of intensive and continuation phase directly observed therapy (DOT) were only 54.7% and 53.0%, respectively. HCWs with high work satisfaction and junior titles were more likely to deliver first-time home visits and DOT services. Our results suggest that barriers to TTMS delivery at the organisational level include limited patient-centred approaches, inadequate resources and incentives, insufficient training, poor cross-sectional coordination, and strict performance assessment. At the patient level, barriers include low socioeconomic status, poor health literacy and TB-related social stigma. CONCLUSION: TTMSs in Southwest China still need further improvement, and this study highlighted specific barriers to TTMS delivery in the PHC sector. Comprehensive measures are urgently needed to address these barriers at the organisational and patient levels to promote TB control in Southwest China.

Factors predicting self-report adherence (SRA) behaviours among DS-TB patients under the "Integrated model": a survey in Southwest China.

BACKGROUND: China is one of 30 countries with a high tuberculosis (TB) burden, and poor adherence to TB treatment is one of the biggest challenges for TB control. We aimed to explore the barriers and facilitators of treatment adherence among drug-sensitive tuberculosis (DS-TB) patients under the "Integrated model" in Western China, to provide evidence-based treatment and control regimens for DS-TB patients to improve adherence behaviours. METHODS: Both qualitative and quantitative research methods were used to explore the factors associated with self-reported adherence (SRA) behaviours. Questionnaire surveys with DS-TB patients and in-depth interviews with leaders from the Centers for Disease Control and Prevention (CDC) and community health sectors (CHCs), healthcare workers (HCWs) from CHCs, and DS-TB patients were conducted. RESULTS: A total of 459 eligible patients were included in the quantitative survey, and two patients and 13 healthcare providers were included in the in-depth interviews. The percentage of patients who experienced a missed dose, lack of follow-up sputum examination, and interrupted treatment were 19.0%, 11.3%, and 9.2%, respectively. Patients aged 20-39 had a higher risk of missed dose [OR (95% CI): 2.302 (1.001-5.305)] and a lower risk of interrupted treatment [OR (95% CI): 0.278 (0.077-0.982)] than patients more than 60 years. Patients who were of Han ethnicity (OR [95% CI]: 0.524 [0.301-0.912]) received psychological support (OR [95% CI]: 0.379 [0.144-0.998]) from their family and had a lower risk of missed doses. Patients who had drug side effects had a higher risk of interrupted treatment (OR [95% CI]: 2.587 [1.237-5.412]). Patients who possessed higher knowledge had a lower risk of lack of follow-up sputum examination [OR (95% CI): 0.817 (0.673-0.991)]. The results of the qualitative study also reported that patients' poor TB knowledge was the main reason for their non-SRA behaviours. CONCLUSIONS: Patient-centred strategies should be implemented to improve health literacy and strengthen psychological support. More effective case management should be designed and implemented based on different patient characteristics to improve adherence behaviours in further studies.

A Fast and Efficient Approach to Obtaining High-Purity Glioma Stem Cell Culture.

Glioma is the most common and malignant primary brain tumor. Patients with malignant glioma usually have a poor prognosis due to drug resistance and disease relapse. Cancer stem cells contribute to glioma initiation, progression, resistance, and relapse. Hence, quick identification and efficient understanding of glioma stem cells (GSCs) are of profound importance for therapeutic strategies and outcomes. Ideally, therapeutic approaches will only kill cancer stem cells without harming normal neural stem cells (NSCs) that can inhibit GSCs and are often beneficial. It is key to identify the differences between cancer stem cells and normal NSCs. However, reports detailing an efficient and uniform protocol are scarce, as are comparisons between normal neural and cancer stem cells. Here, we compared different protocols and developed a fast and efficient approach to obtaining high-purity glioma stem cell by tracking observation and optimizing culture conditions. We examined the proliferative and differentiative properties confirming the identities of the GSCs with relevant markers such as Ki67, SRY-box containing gene 2, an intermediate filament protein member nestin, glial fibrillary acidic protein, and s100 calcium-binding protein (s100-beta). Finally, we identified distinct expression differences between GSCs and normal NSCs including cyclin-dependent kinase 4 and tumor protein p53. This study comprehensively describes the features of GSCs, their properties, and regulatory genes with expression differences between them and normal stem cells. Effective approaches to quickly obtaining high-quality GSCs from patients should have the potential to not only help understand the diseases and the resistances but also enable target drug screening and personalized medicine for brain tumor treatment.

Determinants of self-management behaviors among pulmonary tuberculosis patients: a path analysis.

BACKGROUND: Tuberculosis (TB) is one of the top 10 causes of death in the world. Since Directly Observed Therapy (DOT) as a core strategy for the global TB control are not applicable to all types of TB patients, and self-management of TB patients (SMTP) as a patient-centered supervision type is a supplement to DOT and can improve TB case management. However, the factors related to SMTP are complex and need more study. This study aimed at identifying the determinants of SMTP and examining the direct/indirect effects of these determinants. METHODS: The purposive sampling technique was used to select study sites and participants were recruited from the study sites by the consecutive sampling method. The PRECEDE model was used as the framework to analyze the determinants of SMTP. The responses of TB patients were acquired via a questionnaire survey for data collection. A Pearson correlation analysis was used to define the relationship between the predisposing, enabling, reinforcing factors with SMTP behaviors. A regression-based path analysis was used to determine the action paths of the predisposing, enabling, and reinforcing factors on SMTP behaviors. RESULTS: The predisposing (TB knowledge), enabling [health education and healthcare workers (HCWs) support], reinforcing factors (family support) had significant positive correlations with SMTP behaviors (P < 0.05). The predisposing, enabling, reinforcing factors were positively correlated with each other (r = 0.123‒0.918, P < 0.05), except for family support and HCWs support. The predisposing factors (TB knowledge, ß = 0.330) and the enabling factors (HCWs support, ß = 0.437) had direct effects on SMTP behaviors. The enabling factors (health education and HCWs support) and the reinforcing factors (family support) had indirect effects on SMTP behaviors. CONCLUSIONS: This study revealed the effects and action path of TB knowledge, health education, HCWs support, and family support on SMTP behaviors via a path analysis. Assessing patient's needs for SMTP along with promoting effective TB health education and providing firm support from HCWs and family members are potential strategies to promote SMTP behaviors.

Adherence to Multidrug Resistant Tuberculosis Treatment and Case Management in Chongqing, China - A Mixed Method Research Study.

AIM: This paper evaluated the treatment adherence for multidrug-resistant tuberculosis (MDR-TB) and MDR-TB case management (MTCM) in Chongqing, China in order to identify factors associated with poor treatment adherence and case management. METHODS: Surveys with 132 MDR-TB patients and six in-depth interviews with health care workers (HCWs) from primary health centers (PHC), doctors from MDR-TB designated hospitals and MDR-TB patients were conducted. Surveys collected demographic and socio-economic characteristics, as well as factors associated with treatment and case management. In-depth interviews gathered information on treatment and case management experience and adherence behaviors. RESULTS: Patient surveys found the two main reasons for poor adherence were negative side-effects from the treatment and busy work schedules. In-depth interviews with key stakeholders found that self-perceived symptom improvement, negative side-effects from treatment and financial difficulties were the main reasons for poor adherence. MDR-TB patients from urban areas, who were unmarried, were female, had migrant status, and whose treatments were supervised by health care workers from primary health clinics, had poorer treatment adherence (P<0.05). Among the MDR-TB patients surveyed, 86.7% received any type of MTCM in general (received any kind of MTCM from HCWs in PHC, MDR-TB designated hospital and centers of disease control/TB dispensaries and 62.50% received MTCM from HCWs in PHC sectors). Patients from suburban areas were more likely to receive both MTCM in general (OR=6.70) and MTCM from HCWs in MDR-TB designated hospitals (OR=2.77), but female patients (OR=0.26) were less likely to receive MTCM from HCWs in PHC sectors, and patients who were not educated about MTCM by TB doctors in designated hospitals were less likely to receive MTCM in general (OR=0.14). Patients who had not been hospitalized were less likely to receive MTCM from HCWs in MDR-TB designated hospitals (OR=0.21). CONCLUSION: Stronger MTCM by HCWs in PHC sectors would improve treatment adherence among MDR-TB patients. Community-based patient-centered models of MTCM in PHC sectors and the use of digital health technology could help to improve case management and thereby improve adherence.

Genotyping and Molecular Characterization of Fluoroquinolone's Resistance Among Multidrug-Resistant Mycobacterium tuberculosis in Southwest of China.

Although fluoroquinolones (FQs) are the backbone drugs for the treatment of multidrug-resistant tuberculosis (MDR-TB), the knowledge about the resistance pattern and molecular characterization of new-generation FQs in Chongqing is limited. This study aimed to investigate the resistance rate and mutation types of later-generation FQs against MDR-TB in Chongqing, and further to explore the relationship between different genotypes and phenotypes. A total of 967 clinical strains were characterized using multilocus sequence typing and drug susceptibility testing, followed by analysis of genotype/phenotype association. The 229 (23.7%, 229/967) isolates were identified as MDR-TB. The most effective agent against MDR-TB was gatifloxacin (GFX) (20.1%, 46/229), and the highest resistant rate was observed in ofloxacin (OFX) (41.0%, 94/229). Of the 190 strains (83.0%) identified as Beijing genotype, 111 isolates were modern Beijing genotype (58.4%) and 79 isolates were ancient Beijing genotype (41.6%). By analyzing 94 OFX-resistant isolates, 13 isolates were clustered with the cumulative clustering rate of 13.8% (13/94). Of the 91 isolates (39.7%, 91/229) with a mutation in gyrA gene, mutation in codon 94 was the most prevalent. Only 15 isolates (6.6%, 15/229) harbored a mutation in gyrB gene. There was no significant difference in the mutation rate of gyrA gene between Beijing and non-Beijing genotype, clustered isolates, and nonclustered isolates (p > 0.05).

Spatial-temporal analysis of tuberculosis in Chongqing, China 2011-2018.

BACKGROUND: China is a country with a high burden of pulmonary tuberculosis (PTB). Chongqing is in the southwest of China, where the notification rate of PTB ranks tenth in China. This study analyzed the temporal and spatial distribution characteristics of PTB in Chongqing in order to improve TB control measures. METHODS: A spatial-temporal analysis has been performed based on the data of PTB from 2011 to 2018, which was extracted from the National Surveillance System. The effect of TB control was measured by variation trend of pathogenic positive PTB notification rate and total TB notification rate. Time series, spatial autonomic correlation and spatial-temporal scanning methods were used to identify the temporal trends and spatial patterns at county level. RESULTS: A total of 188,528 cases were included in this study. A downward trend was observed in PTB between 2011 and 2018 in Chongqing. The peak of PTB notification occurred in late winter and early spring annually. By calculating the value of Global Moran's I and Local Getis's Gi*, we found that PTB was spatially clustered and some significant hot spots were detected in the southeast and northeast of Chongqing. One most likely cluster and three secondary clusters were identified by Kulldorff's scan spatial-temporal Statistic. CONCLUSIONS: This study identified seasonal patterns and spatial-temporal clusters of PTB cases in Chongqing. Priorities should be given to southeast and northeast of Chongqing for better TB control.

miR-29a Promotes the Neurite Outgrowth of Rat Neural Stem Cells by Targeting Extracellular Matrix to Repair Brain Injury.

Neural stem cells (NSCs) can generate new neurons to repair brain injury and central nervous system disease by promoting neural regeneration. MicroRNAs (miRNAs) involve in neural development, brain damage, and neurological diseases repair. Recent reports show that several miRNAs express in NSCs and are important to neurogenesis. Neurites play a key role in NSC-related neurogenesis. However, the mechanism of NSC neurite generation is rarely studied. We surprisingly noticed that the neurites increased after bone morphogenetic protein (BMP) treatment in rat NSCs. This process was accompanied by the dynamic change of miRNA-29. Then we discovered that miR-29a regulated neural neurites in rat hippocampus NSCs. Overexpression of miR-29a reduced the cell soma area and promoted the neurite outgrowth of NSCs. Cell soma area became small, whereas the number of neurite increased. Moreover, neurite complexity increased dramatically, with more primary and secondary branches after miR-29a overexpression. In addition, miR-29a overexpression still maintained the stemness of NSCs. Besides, we identified that miR-29a can promote the neurite outgrowth by targeting extracellular matrix-related genes like Fibrillin 1 (Fbn1), Follistatin-like 1 (Fstl1), and laminin subunit gamma 2 (Lamc2). These findings may provide a novel role of miR-29a to regulate neurite outgrowth and development of NSCs. We also offered a possible theoretical basis to the migration mechanism of NSCs in brain development and damage repair.

Epidemiology of drug-resistant tuberculosis in Chongqing, China: A retrospective observational study from 2010 to 2017.

China is one of the top 30 countries with high multidrug-resistant tuberculosis (MDR-TB) and rifampin-resistant tuberculosis (RR-TB) burden. Chongqing is a southwest city of China with a large rural population. A retrospective observational study has been performed based on routine tuberculosis (TB) surveillance data in Chongqing from 2010 to 2017. The MDR/RR-TB notification rate increased from 0.03 cases per 100,000 population in 2010 to 2.1 cases per 100,000 population in 2017. The extensively drug-resistant TB (XDR-TB) notification rate has increased to 0.09 cases per 100,000 population in 2017. There was a decreasing detection gap between the number of notified MDR/RR-TB cases and the estimate number of MDR/RR-TB cases in new TB cases. The treatment success rate of MDR/RR-TB was 59% (95% confidence interval [CI], 53%-65%) in this period. Despite the progress achieved, the prevalence of MDR/RR-TB was still high facing challenges including detection gaps in new TB cases, the regional disparity, and the high risk for MDR/RR-TB in elderly people and farmers. Sustained government financing and policy support should be guaranteed in the future.

Extent and determinants of catastrophic health expenditure for tuberculosis care in Chongqing municipality, China: a cross-sectional study.

OBJECTIVE: To investigate the extent and associations of patient/diagnostic delay and other potential factors with catastrophic health expenditure (CHE) for tuberculosis (TB) care in Chongqing municipality, China. DESIGN: A cross-sectional study. SETTING: Four counties of Chongqing municipality, China. PARTICIPANTS: A total of 1199 patients with active pulmonary TB beyond 16 years and without mental disorders were consecutively recruited in the four counties' designated TB medical institutions. OUTCOME MEASURES: The incidence and intensity of CHE for TB care were described. The association between patients' 'sociodemographic and clinical characteristics such as patient delay, diagnostic delay, forms of TB, health insurance status and hospitalisation and CHE were analysed using univariate and multivariate logistic regression. RESULTS: The incidence of CHE was 52.8% and out-of-pocket (OOP) payments were 93% of the total costs for TB care. Compared with patients without delay, the incidence and intensity of CHE were higher in patients who had patient delay or diagnostic delay. Patients who experienced patient delay or diagnostic delay, who was a male, elderly (≥60 years), an inhabitant, a peasant, divorced/widow, the New Cooperative Medical Scheme membership had greater risks of incurring CHE for TB care. Having a higher educational level appeared to be a protective factor. However, hospitalisation was not associated with CHE after controlling for other variables. CONCLUSION: The incidence and intensity of CHE for TB care are high, which provides baseline data about catastrophic costs that TB-related households faced in Chongqing of China. Variety of determinants of CHE implicate that it is essential to take effective measures to promote early seeking care and early diagnosis, improve the actual reimbursement rates of health insurance, especially for outpatients, and need more fine-tuned interventions such as precise poverty alleviation to reduce catastrophic costs of the vulnerable population.

Efficient and Fast Differentiation of Human Neural Stem Cells from Human Embryonic Stem Cells for Cell Therapy.

Stem cell-based therapies have been used for repairing damaged brain tissue and helping functional recovery after brain injury. Aberrance neurogenesis is related with brain injury, and multipotential neural stem cells from human embryonic stem (hES) cells provide a great promise for cell replacement therapies. Optimized protocols for neural differentiation are necessary to produce functional human neural stem cells (hNSCs) for cell therapy. However, the qualified procedure is scarce and detailed features of hNSCs originated from hES cells are still unclear. In this study, we developed a method to obtain hNSCs from hES cells, by which we could harvest abundant hNSCs in a relatively short time. Then, we examined the expression of pluripotent and multipotent marker genes through immunostaining and confirmed differentiation potential of the differentiated hNSCs. Furthermore, we analyzed the mitotic activity of these hNSCs. In this report, we provided comprehensive features of hNSCs and delivered the knowledge about how to obtain more high-quality hNSCs from hES cells which may help to accelerate the NSC-based therapies in brain injury treatment.

Epidemiology of tuberculosis in Chongqing, China: a secular trend from 1992 to 2015.

Chongqing is a southwest city of China with high tuberculosis (TB) burden. An observational retrospective study has been performed based on routine TB surveillance data in Chongqing from 1992 to 2015. The TB notification rate has declined to 70.8 cases per 100,000 population from the peak of 106 cases per 100,000 in 2005. The TB notification rate in population over-65 years has become the highest among all-ages population since 2010. The average proportion of farmers in all notified cases from 2008 to 2015 was 62.5%, and the notification rate of farmers has become the highest among all occupations since 2011. The TB notification showed a regional disparity in Chongqing. Despite the improvement achieved since 1992, the TB control efforts has been threatened by new challenges such as the demographic shift towards an aging population, the prevalence of MDR-TB and TB/HIV co-infection, and the regional disparity of TB notification. More effective interventions should be implemented. Our study can serve as a guidance for the future development of TB control in Chongqing, and we believe it has general relevance to TB control in other regions with similar situations.

High expression of TIG3 predicts poor survival in patients with primary glioblastoma.

TIG3 (tazarotene-induced gene 3) has been reported to suppress the progression of several malignancies, where this gene is universally downregulated. However, the expression of TIG3 in primary glioblastoma and its relevance to patient's prognosis have not been elaborated. Thus, this study was aimed to evaluate TIG3 expression level in primary glioblastoma and investigate the prognostic value of TIG3 for patients. The Cancer Genome Atlas database was first utilized to analyze the expression and prognostic potential of TIG3 in 528 glioblastoma cases. Compared with control group, glioblastoma showed significantly elevated TIG3 expression (p < 0.001). Log-rank analysis revealed that higher expression of TIG3 was associated with shorter overall survival (358vs 383 days, p = 0.039). Furthermore, TIG3 protein expression detected by immunohistochemistry confirmed positive correlation of TIG3 expression and glioma grade and upregulation of TIG3 in our cohort of 101 primary glioblastoma patients compared to 16 normal brains. Finally, Kaplan-Meier analysis and Cox regression analysis identified high TIG3 expression as an independent risk factor for overall survival of primary glioblastoma patients (overall survival, 10 vs 13 months, p = 0.033; hazard ratio = 1.542, p = 0.046). Together, this study indicated that increased expression of TIG3 in primary glioblastoma is a novel biomarker for predicting poor outcome of patients. We then hypothesize that TIG3 may function in a different pattern in glioblastoma.

Later emergence of acquired drug resistance and its effect on treatment outcome in patients treated with Standard Short-Course Chemotherapy for tuberculosis.

BACKGROUNDS: The failure of current Standard Short-Course Chemotherapy (SCC) in new and previously treated cases with tuberculosis (TB) was mainly due to drug resistance development. But little is known on the characteristics of acquired drug resistant TB during SCC and its correlation with SCC failure. The objective of the study is to explore the traits of acquired drug resistant TB emergence and evaluate their impacts on treatment outcomes. METHODS: A prospective observational study was performed on newly admitted smear positive pulmonary TB (PTB) cases without drug resistance pretreatment treated with SCC under China's National TB Control Program (NTP) condition from 2008 to 2010. Enrolled cases were followed up through sputum smear, culture and drug susceptibility testing (DST) at the end of 1, 2, and 5 months after treatment initiation. The effect factors of early or late emergence of acquired drug resistant TB , such as acquired drug resistance patterns, the number of acquired resistant drugs and previous treatment history were investigated by multivariate logistic regression; and the impact of acquired drug resistant TB emergence on treatment failure were further evaluated. RESULTS: Among 1671 enrolled new and previously treated cases with SCC, 62 (3.7%) acquired different patterns of drug resistant TB at early period within 2 months or later around 3-5 months of treatment. Previously treated cases were more likely to develop acquired multi-drug resistant TB (MDR-TB) (OR, 3.8; 95%CI, 1.4-10.4; P = 0.015). Additionally, acquired MDR-TB cases were more likely to emerge at later period around 3-5 months after treatment starting than that of non-MDR-TB mainly appeared within 2 months (OR, 8.3; 95%CI, 1.7-39.9; P = 0.008). Treatment failure was associated with late acquired drug resistant TB emergence (OR, 25.7; 95%CI, 4.3-153.4; P < 0.001) with the reference of early acquired drug resistant TB emergence. CONCLUSIONS: This study demonstrates that later development of acquired drug resistant TB during SCC is liable to suffer treatment failure and acquired MDR-TB pattern may be one of the possible causes.

Framework of behavioral indicators evaluating TB health promotion outcomes: a modified Delphi study of TB policymakers and health workers.

BACKGROUND: Although TB health promotion directed at policy makers and healthcare workers (HCWs) is considered important to tuberculosis (TB) control, no indicators currently assess the impact of such promotional activities. This article is the second in a series of papers that seek to establish a framework of behavioral indicators for outcome evaluation of TB health promotion, using the Delphi method. In the first article, we sought to establish a framework of behavioral indicators for outcome evaluation of TB health promotion among TB suspects and patients. The objective of this second article is to present an indicator framework that can be used to assess behavioral outcomes of TB health promotion directed at policy makers and HCWs. METHODS: A two-round, modified Delphi method was used to establish the indicators. Sixteen experts who were knowledgeable and experienced in the field of TB control were consulted in Delphi surveys. A questionnaire was developed following 4 steps, and involved ranking indicators on a five-point Likert scale. The consensus level was 70 %. Median, mode, and Coefficient of variation (CV) were used to describe expert responses. An authority coefficient (Cr) was used to assess the degree of each expert's authority. RESULTS: Consensus was achieved following the two survey rounds and several iterations among the experts. For TB health-promotion activities directed at policymakers, the experts reached consensus on 2 domains ("Resource inputs" and "Policymaking and monitoring behaviors"), 4 subdomains ("Human resources" among others), and 13 indicators ("Human resources per 100,000 person" among others). For TB health-promotion activities directed at HCWs, the experts reached consensus on 5 domains ("Self-protective behaviors" among others), 6 sub-domains ("Preventing infection" among others), and 15 indicators ("Average hours of daily workplace disinfection by ultraviolet radiation" among others). CONCLUSIONS: This study identified a conceptual framework of core behavioral indicators to evaluate TB health-promotion activities directed at policymakers and HCWs involved in TB control. Validation in other parts of the world could lead to global consensus on behavioral indicators to evaluate TB health promotion targeted at policymakers and HCWs.