NIR Activated Multimodal Therapeutics Based on Metal-Phenolic Networks-Functionalized Nanoplatform for Combating against Multidrug Resistance and Metastasis.

Multidrug resistance (MDR) and metastasis in cancer have become increasingly serious problems since antitumor efficiency is greatly restricted by a single therapeutic modality and the insensitive tumor microenvironment (TME). Herein, metal-phenolic network-functionalized nanoparticles (t-P@TFP NPs) are designed to realize multiple therapeutic modalities and reshape the TME from insensitive to sensitive under multimodal imaging monitoring. After a single irradiation, a near-infrared laser-activated multistage reaction occurs. t-P@TFP NPs trigger the phase transition of perfluoropentane (PFP) to release tannic acid (TA)/ferric ion (Fe3+ )-coated paclitaxel (PTX) and cause hyperthermia in the tumor region to efficiently kill cancer cells. Additionally, PTX is released after the disassembly of the TA-Fe3+ film by the abundant adenosine triphosphate (ATP) in the malignant tumor, which concurrently inhibits ATP-dependent drug efflux to improve sensitivity to chemotherapeutic agents. Furthermore, hyperthermia-induced immunogenic cell death (ICD) transforms "cold" tumors into "hot" tumors with the assistance of PD-1/PD-L1 blockade to evoke antitumor immunogenicity. This work carefully reveals the mechanisms underlying the abilities of these multifunctional NPs, providing new insights into combating the proliferation and metastasis of multidrug-resistant tumors.

Factors affecting time to treatment initiation after diagnosis for multidrug-resistant/rifampicin-resistant tuberculosis patients: A mixed-methods study in Jakarta, Indonesia.

OBJECTIVE: To investigate the time to treatment initiation (TTI) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) patients after diagnosis in Indonesia and biological, psychological and social factors associated with the time interval. METHODS: This study was conducted in Persahabatan Hospital, Jakarta using a mixed-methods approach. Registry data and medical records of MDR/RR-TB patients were collected and matched (hospital dataset), and linked with psychosocial assessment results (linked dataset). Descriptive analysis was conducted to understand patient characteristics and the distribution of TTI after RR-TB diagnosis by GeneXpert. Generalised linear regression was used to analyse factors associated with delay duration, and logistic regression to explore factors associated with the delay longer than the median duration for both datasets (basic vs. extended model). In-depth interviews were conducted with patients and healthcare workers to understand the procedure of treatment initiation and how different factors led to delay. RESULTS: The hospital dataset included 275 patient-matched cases, and 188 were further linked with psychosocial assessment results. The median time interval was 24 days [interquartile range (IQR) 23.5] and 26 days (IQR 21.25), respectively. Regression analysis showed that in the extended model, comorbidities (exp [coefficient]= 1.93), unemployment (exp [coefficient] = 1.80) and poor knowledge of MDR/RR-TB (exp (coefficient) = 1.67) seemed to have the strongest effects on prolonging the time interval (p < 0.05). Unsuccessful TB treatment history was the only factor that significantly increased the risk of delay longer than the median duration (p < 0.05) in the basic model, while none of the factors were significant in the extended model. The qualitative study identified provider-side factors (centralised service provision and insufficient human resources) and patient-side factors (physical weakness, psychological stress and financial concern) associated with treatment delay. CONCLUSION: MDR/RR-TB patients in Persahabatan Hospital, Jakarta, Indonesia waited around 25 days for treatment initiation after RR-TB diagnosis. Health system solutions are needed to address challenges facing both MDR/RR-TB patients and healthcare providers to reduce delay in treatment initiation.

Tumor-penetrating nanoplatform with ultrasound "unlocking" for cascade synergistic therapy and visual feedback under hypoxia.

BACKGROUND: Combined therapy based on the effects of cascade reactions of nanoplatforms to combat specific solid tumor microenvironments is considered a cancer treatment strategy with transformative clinical value. Unfortunately, an insufficient O2 supply and the lack of a visual indication hinder further applications of most nanoplatforms for solid tumor therapy. RESULTS: A visualizable nanoplatform of liposome nanoparticles loaded with GOD, H(Gd), and PFP and grafted with the peptide tLyP-1, named tLyP-1H(Gd)-GOD@PFP, was constructed. The double-domain peptide tLyP-1 was used to specifically target and penetrate the tumor cells; then, US imaging, starvation therapy and sonodynamic therapy (SDT) were then achieved by the ultrasound (US)-activated cavitation effect under the guidance of MR/PA imaging. GOD not only deprived the glucose for starvation therapy but also produced H2O2, which in coordination with 1O2 produced by H(Gd), enable the effects of SDT to achieve a synergistic therapeutic effect. Moreover, the synergistic therapy was enhanced by O2 from PFP and low-intensity focused ultrasound (LIFU)-accelerated redox effects of the GOD. The present study demonstrated that the nanoplatform could generate a 3.3-fold increase in ROS, produce a 1.5-fold increase in the maximum rate of redox reactions and a 2.3-fold increase in the O2 supply in vitro, and achieve significant tumor inhibition in vivo. CONCLUSION: We present a visualizable nanoplatform with tumor-penetrating ability that can be unlocked by US to overcome the current treatment problems by improving the controllability of the O2 supply, which ultimately synergistically enhanced cascade therapy.

Behavioral trigger factors for hemorrhagic stroke: a case-crossover study.

BACKGROUND: The role and extent of the effects of short-term behavioral factors on the risk of hemorrhagic stroke (HS) are unclear. This study aimed to assess and quantify behavioral trigger factors (BTFs) for HS and identify the differences in BTFs between Chinese and other populations. METHODS: A case-crossover study was performed from March 2021 to February 2022. New-onset HS patients were recruited from two university hospitals in China. The patients were interviewed to evaluate their exposure to 20 potential BTFs during the predefined risk and control periods and to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). A comprehensive literature review was conducted to synthesize the evidence. RESULTS: A total of 284 patients with HS were included (150 with intracerebral hemorrhage and 134 with subarachnoid hemorrhage). Multivariate regression analysis showed that straining for defecation (OR: 3.06; 95% CI: 1.01-8.40), weightlifting (OR: 4.82; 95% CI: 1.02-22.83), overeating (OR: 4.33; 95% CI: 1.24-15.21), heavy physical exertion (OR: 3.02; 95% CI: 1.18-7.78), and chess/cards/mahjong games (OR: 2.51; 95% CI: 1.05-6.01) were associated with an increased risk within 2 hours before HS onset, and critical life events (OR: 3.81; 95% CI: 1.06-13.74) were associated with an increased risk 7 days before the onset of HS. Exposure to anger (OR: 3.17; 95% CI: 1.73-5.81) and heavy physical exertion (OR: 2.12; 95% CI: 1.65, 2.74) showed an increased risk of HS events after the pooled analysis. CONCLUSIONS: Several behavioral activities and mood modifications are associated with the onset of HS. In addition to the common BTFs, Chinese patients have specific BTFs due to their habits and customs distinct from those of different populations in other regions. Key messages What is already known on this topic It is known that several behavioral trigger factors (BTFs) are associated with the onset of hemorrhagic stroke (HS), such as vigorous physical exercise and anger. Evidence for other potential trigger factors was of less robustness. Which BTFs contribute to HS among the Chinese population is poorly understood, since individuals in different countries and regions have their own habits of life and customs. What this study adds Our study identified that two special behaviors, chess/card/mahjong games and critical life events, were associated with the onset of HS in Chinese populations, besides heavy physical exertion, weightlifting, overeating, and straining for defecation, which were previously reported in other populations. Heavy physical exertion and anger could potentially increase the risk of HS based on a comprehensive aggregation and evidence synthesis. How this study might affect research, practice, or policy Patients in different populations or regions may possess specific BTFs owing to their distinct habits and customs. Avoidance of these behaviors and regulation of emotions to maintain a steady mentality would help minimize exposure and prevent the disease for high-risk populations in China.

The co-management of tuberculosis-diabetes co-morbidities in Indonesia under the National Tuberculosis Control Program: results from a cross-sectional study from 2017 to 2019.

BACKGROUND: Indonesia suffers from a high burden of tuberculosis (TB) and diabetes (DM). The government initiated national TB-DM co-management activities under the National TB Control Program in 2017. This study investigates the detection and treatment outcomes of TB-DM in Jakarta after implementing these activities, and identifies the main factors associated with these outcomes. METHODS: A cross-sectional study was conducted using TB registry data in two districts of Jakarta, East Jakarta (low-income) and South Jakarta (high-income). A 5-step cascade analysis was used: diagnosed TB patients; TB patients tested for DM; diagnosed TB-DM patients; and patients received and completed TB treatment/cured. We conducted descriptive analyses to understand the characteristics of TB and TB-DM patients, and used a two-level mixed-effect logistic regression to explore factors associated with having a DM test and completing TB treatment/being cured. RESULTS: Over the study period (2017-2019) 50.8% of the new pulmonary TB patients aged over 15 were tested for DM. The percentage increased from 41.7% in 2017-2018 to 60.1% in 2019. Of the TB patients tested for DM, 20.8% were diagnosed with DM. Over 90% of the detected TB-DM patients received standard TB treatment, 86.3% of whom completed treatment/were cured. Patients in East Jakarta were more likely to be tested for DM and to complete standard TB treatment/be cured than patients in South Jakarta (P <  0.001). Bacteriologically positive TB patients were more likely to be tested for DM (OR = 1.37, 95% CIs 1.17,1.60). Patients diagnosed in sub-district level healthcare centers had a higher likelihood of being tested for DM than those in government and private hospitals (P <  0.05). Receiving DM treatment was associated with a higher likelihood of completing TB treatment/being cured (OR = 1.82, 95% CIs 1.20, 2.77). CONCLUSIONS: TB-DM case detection significantly improved in 2019 after introducing TB-DM co-management activities in Jakarta, while gaps in TB-DM co-management existed between bacteriologically positive and clinically diagnosed TB patients, and across different types of health facilities. Collaboration between TB and DM departments should be strengthened, and more resources need to be mobilized to further improve the co-management of TB-DM in Indonesia.

Knockdown lncRNA CRNDE enhances temozolomide chemosensitivity by regulating autophagy in glioblastoma.

BACKGROUND: The regulatory roles of long non-coding RNA (lncRNA) CRNDE in temozolomide (TMZ) chemoresistance to glioblastoma multiforme (GBM) are still poorly understood. Therefore, the function, characteristics, and possible mechanism of CRNDE in TMZ-induced chemoresistance to GBM were explored. METHODS: Firstly, the expression level of CRNDE in 58 cases of glioma tissue specimens and 30 cases of normal brain tissues were tested by qRT-PCR. Meanwhile, the correlation between CRNDE expression level, the clinicopathological characteristics, and survival time of patients with glioma were analyzed. Then, the CRNDE expression in various glioma cell lines was detected, and CRNDE knockdown cell models were constructed. Subsequently, to explore the effect of CRNDE on chemosensitivity to TMZ, cell viability was detected by the CCK-8 assay and IC50 values, and cell proliferation was detected by cell clone assay and EdU assay, as well as cell survival was detected by apoptosis with flow cytometry under TMZ treatment. Further, the expression of drug-resistance protein ABCG2, autophagy related proteins, and PI3K/Akt/mTOR pathway were measured by western blot or qRT-PCR in TMZ-treated glioma cells. Finally, the mouse tumor xenograft model was established and the tumor volume and weight were measured, and ABCG2 expression was conducted by immunohistochemistry assay. RESULTS: The integrated results demonstrated lncRNA CRNDE was a poor prognosis factor for GBM patient, which was upregulated in patients who were resistant to TMZ, and closely associated with chemotherapeutic response status to TMZ treatment. Further, functional assays revealed that knockdown of CRNDE could notably reduce glioma cell viability and proliferation, and elevate cell apoptosis to enhance the chemosensitivity to TMZ in vitro and in vivo. Mechanistically, the depression of CRNDE could diminish the expression of LC3 II/I, Beclin1 and Atg5 and increase the p62 expression level to inhibit autophagy due to the activation of PI3K/Akt/mTOR pathway as well as highly correlated with ABCG2 expression. CONCLUSIONS: Overall, the study provided that lncRNA CRNDE is a reliable clinical predictor of outcome and prognosis and a potential biomarker for predicting TMZ treatment response in GBM by modulating the autophagy through PI3K/Akt/mTOR pathway and ABCG2 expression which may be a novel therapeutic target for regulating TMZ sensitivity to GBM.

Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based "combo" nanoagent together with PD-L1 blockade in reversing multidrug resistance.

BACKGROUND: Recent studies have demonstrated that multidrug resistance (MDR) is a critical factor in the low efficacy of cancer chemotherapy. The main mechanism of MDR arises from the overexpression of P-glycoprotein (P-gp), which actively enhances drug efflux and limits the effectiveness of chemotherapeutic agents. RESULTS: In this study, we fabricated a "combo" nanoagent equipping with triple synergistic strategies for enhancing antitumor efficacy against MDR cells. Tumor homing-penetrating peptide endows the nanosystem with targeting and penetrating capabilities in the first stage of tumor internalization. The abundant amine groups of polyethylenimine (PEI)-modified nanoparticles then trigger a proton sponge effect to promote endo/lysosomal escape, which enhances the intracellular accumulation and retention of anticancer drugs. Furthermore, copper tetrakis(4-carboxyphenyl)porphyrin (CuTCPP) encapsulated in the nanosystem, effectively scavenges endogenous glutathione (GSH) to reduce the detoxification mediated by GSH and sensitize the cancer cells to drugs, while simultaneously serving as a photoacoustic imaging (PAI) contrast agent for image visualization. Moreover, we also verify that these versatile nanoparticles in combination with PD-1/PD-L1 blockade therapy can not only activate immunological responses but also inhibit P-gp expression to obliterate primary and metastatic tumors. CONCLUSION: This work shows a significant enhancement in therapeutic efficacy against MDR cells and syngeneic tumors by using multiple MDR reversing strategies compared to an equivalent dose of free paclitaxel.

[Progression on Multifunctional Nanoparticles Interfering with Cell Membrane Transporters-associated Drug Resistance].

Multi-drug resistance(MDR)refers to the loss of sensitivity of tumor cells to traditional chemotherapeutics agents under the mediation of various mechanisms,resulting in the reduction of chemotherapy efficacy.Current studies suggest that a variety of factors,including cell membrane transporter-mediated efflux of anti-tumor drugs,special microenvironment in tumor tissue,DNA self-repair and anti-apoptotic process,and epithelial-mesenchymal cell transformation,may contribute to the formation of MDR.Cell membrane transporter-mediated drug efflux refers to an increase in the amount of anti-tumor drug pumped out of the cell through the up-regulation of the ATP-binding cassette transporter on tumor cell membrane,which reduces the concentration of the drug in the cell,thus forming MDR.An effective method to inhibit the efflux pump caused by overexpression of membrane transporters plays an important role in overcoming MDR.As a promising drug delivery system,multifunctional nanoparticles have demonstrated many advantages in antitumor therapy.Meanwhile,nanoparticles with tailored design are capable of overcoming MDR when combined with a variety of strategies.This paper described in detail the studies relevant to the use of multifunctional nano-sized drug delivery system combined with different strategies,such as co-delivery of agents,external responsiveness or target modification for intervention with efflux pump in order to reverse MDR.This paper provides reference for the development of nano-sized drug delivery system and the formulation of reversal strategy in the future.

Progress in the role of high resolution magnetic resonance imaging technology in the risk assessment of intracranial aneurysm rupture. / é«˜åˆ†è¾¨çŽ‡ç£å ±æŒ¯æˆåƒæŠ€æœ¯è¯„ä¼°é¢ å† åŠ¨è„‰ç˜¤ç ´è£‚é£Žé™©çš„ç ”ç©¶è¿›å±•.

The traditional classification, diagnosis, and treatment of intracranial aneurysms are based on the characteristics of their vascular lumen. However, in the past few years, some advances in MRI technology with high-resolution imaging can assess the pathology of intracranial vascular walls. Compared with traditional methods of computed tomography angiography, magnetic resonance angiograhpy, and digital subtraction angiography, high resolution magnetic resonance imaging technology can help us to newly understand the disease by directly evaluating the characteristics of vascular wall, such as aneurysm wall thickness, inflammation, enhancement, permeability and hemodynamics. At present, high-resolution magnetic resonance imaging is increasingly used in clinic to assess the rupture risk of intracranial aneurysms, which is of great significance for guiding the diagnosis and treatment of intracranial aneurysms.

Current situation and progress toward the 2030 health-related Sustainable Development Goals in China: A systematic analysis.

BACKGROUND: The Sustainable Development Goals (SDGs), adopted by all United Nations (UN) member states in 2015, established a set of bold and ambitious health-related targets to achieve by 2030. Understanding China's progress toward these targets is critical to improving population health for its 1.4 billion people. METHODS AND FINDINGS: We used estimates from the Global Burden of Disease (GBD) Study 2016, national surveys and surveillance data from China, and qualitative data. Twenty-eight of the 37 indicators included in the GBD Study 2016 were analyzed. We developed an attainment index of health-related SDGs, a scale of 0-100 based on the values of indicators. The projection model is adjusted based on the one developed by the GBD Study 2016 SDG collaborators. We found that China has achieved several health-related SDG targets, including decreasing neonatal and under-5 mortality rates and the maternal mortality ratios and reducing wasting and stunting for children. However, China may only achieve 12 out of the 28 health-related SDG targets by 2030. The number of target indicators achieved varies among provinces and municipalities. In 2016, among the seven measured health domains, China performed best in child nutrition and maternal and child health and reproductive health, with the attainment index scores of 93.0 and 91.8, respectively, followed by noncommunicable diseases (NCDs) (69.4), road injuries (63.6), infectious diseases (63.0), environmental health (62.9), and universal health coverage (UHC) (54.4). There are daunting challenges to achieve the targets for child overweight, infectious diseases, NCD risk factors, and environmental exposure factors. China will also have a formidable challenge in achieving UHC, particularly in ensuring access to essential healthcare for all and providing adequate financial protection. The attainment index of child nutrition is projected to drop to 80.5 by 2025 because of worsening child overweight. The index of NCD risk factors is projected to drop to 38.8 by 2025. Regional disparities are substantial, with eastern provinces generally performing better than central and western provinces. Sex disparities are clear, with men at higher risk of excess mortality than women. The primary limitations of this study are the limited data availability and quality for several indicators and the adoption of "business-as-usual" projection methods. CONCLUSION: The study found that China has made good progress in improving population health, but challenges lie ahead. China has substantially improved the health of children and women and will continue to make good progress, although geographic disparities remain a great challenge. Meanwhile, China faced challenges in NCDs, mental health, and some infectious diseases. Poor control of health risk factors and worsening environmental threats have posed difficulties in further health improvement. Meanwhile, an inefficient health system is a barrier to tackling these challenges among such a rapidly aging population. The eastern provinces are predicted to perform better than the central and western provinces, and women are predicted to be more likely than men to achieve these targets by 2030. In order to make good progress, China must take a series of concerted actions, including more investments in public goods and services for health and redressing the intracountry inequities.

Over- and under-treatment of TB patients in Eastern China: an analysis based on health insurance claims data.

OBJECTIVE: Poor compliance with existing guidelines for tuberculosis (TB) care and treatment is an issue of concern in China. We assessed health service use by TB patients over the entire treatment process and compared it to the recommended guidelines. METHODS: We collected insurance claims data in three counties of one province of Eastern China. Patient records with a diagnosis of 'pulmonary TB' in 2015 and 2016 were extracted. Treatment duration, number of outpatient (OP) visits and hospital admissions, as well as total cost, out-of-pocket (OOP) payments and effective reimbursement rates were analysed. RESULTS: A total of 1394 patients were included in the analysis. More than 48% received over the 8 months of treatment that TB guidelines recommend, and over 28% received less. 49% of Urban and Rural Resident Basic Medical Insurance (URRBMI) TB patients were hospitalised while 30% of those with Urban Employee Basic Medical Insurance (UEBMI) had at least one admission. Median total cost for patients with hospital admission was almost 10 times that of patients without. By comparison, the average OOP was 5 times higher. UEBMI patients had a shorter treatment period, more outpatient visits but considerably fewer hospital admissions than URRBMI patients. CONCLUSIONS: We found an alarming extent of TB over- and under-treatment in our study population. There is an urgent need to improve compliance with treatment guidelines in China and to better understand the drivers of divergence. Extending the coverage of health insurance schemes and increasing reimbursement rates for TB outpatient services would seem to be key factors in reducing both the overall cost and financial burden on patients.

OBJECTIF: Le mauvais respect des directives existantes en matière de soins et de traitement de la tuberculose (TB) est un sujet préoccupant en Chine. Nous avons évalué l'utilisation des services de santé par les patients TB tout au long du processus de traitement et l'avons comparée aux directives recommandées. MÉTHODES: Nous avons collecté des données sur les réclamations d'assurance dans trois comtés d'une province de l'est de la Chine. Les dossiers de patients avec un diagnostic de «TB pulmonaire¼ en 2015 et 2016 ont été extraits. La durée du traitement, le nombre de visites ambulatoires et d'hospitalisations, ainsi que le coût total, les paiements directs et les taux de remboursement effectifs ont été analysés. RÉSULTATS: 1.394 patients ont été inclus dans l'analyse. Plus de 48% ont reçu plus de 8 mois du traitement recommandé par les directives TB et plus de 28% en ont reçu moins. 49% des patients TB résidents urbains et ruraux de l'assurance médicale de base (URRBMI) ont été hospitalisés, tandis que 30% de ceux avec une assurance médicale de base des employés urbains (UEBMI) ont eu au moins une admission. Le coût total moyen pour les patients hospitalisés était près de 10 fois plus élevé que celui des patients non hospitalisés. En comparaison, le payement direct moyen était 5 fois plus élevé. Les patients UEBMI ont eu une période de traitement plus courte, plus de visites ambulatoires mais beaucoup moins d'hospitalisations que les patients URRBMI. CONCLUSIONS: Nous avons trouvé une étendue alarmante de sur- et sous-traitement de la TB dans notre population d'étude. Il est urgent d'améliorer le respect des directives de traitement en Chine et de mieux comprendre les facteurs de divergence. L'extension de la couverture des schémas d'assurance santé et l'augmentation des taux de remboursement des services ambulatoires pour la TB sembleraient être des facteurs essentiels pour réduire à la fois le coût global et la charge financière pour les patients.

Diagnostic performance of two-dimensional shear wave elastography for evaluating tibial nerve stiffness in patients with diabetic peripheral neuropathy.

OBJECTIVES: To evaluate the stiffness of the tibial nerve with two-dimensional shear wave elastography (2D-SWE) and to determine whether 2D-SWE can be used to diagnose diabetic peripheral neuropathy (DPN). METHODS: The study included 70 consecutive diabetic patients with DPN or without DPN and 20 healthy volunteers. The tibial nerve stiffness measured with 2D-SWE was studied. The differences in stiffness values among patients with DPN, patients with clinically defined DPN, patients without DPN, and healthy volunteers based on clinical features and electrodiagnostic tests were evaluated with the Mann-Whitney U test and the Kruskal-Wallis test. Inter- and intraobserver variability was evaluated, and a receiver operator characteristic curve analysis was performed. RESULTS: The tibial nerve stiffness based on mean (EMean), minimum (EMin), and maximum (EMax) shear elasticity indices was significantly higher in patients with DPN and clinically defined DPN than that in patients without DPN and control subjects (p < 0.05). The area under the curve (AUC) for the SWE measurements of EMean, EMin, and EMax was 0.846, 0.867, and 0.821, respectively. An EMin cutoff value of 45.7 kPa had a sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 74.0%, 87.6%, 6.0, and 0.3, respectively. The inter- and intraobserver agreements were excellent for the SWE measurements. CONCLUSIONS: Tibial nerve stiffness is significantly higher in diabetic patients with DPN and clinically defined DPN. The EMean and EMin have a good accuracy for identifying DPN. Minor degree of peripheral nerve lesions appear to might exist in patients with clinically defined DPN, not detectable by electrophysiology. 2D-SWE has a potential use for cases with clinically defined DPN and can be detected with 2D-SWE. KEY POINTS: • 2D-SWE elastography is a noninvasive method that can be used to evaluate precise nerve stiffness for diagnosing DPN. • Minor degree of neurologic lesion might exist early in patients with clinically defined DPN and can be detected by 2D-SWE. • E Min and E Mean of SWE elasticity indices have better diagnostic accuracies than E Max for identifying DPN.

Transforming tuberculosis (TB) service delivery model in China: issues and challenges for health workforce.

BACKGROUND: China's TB control system has been transforming its service delivery model from CDC (Centers for Disease Control and Prevention)-led model to the designated hospital-led model to combat the high disease burden of TB. The implications of the new service model on TB health workforce development remained unclear. This study aims to identify implications of the new service model on TB health workforce development and to analyze whether the new service model has been well equipped with appropriate health workforce. METHODS: The study applied mixed methods in Zhejiang, Jilin, and Ningxia provinces of China. Institutional survey on designated hospitals and CDC was conducted to measure the number of TB health workers. Individual questionnaire survey was conducted to measure the composition, income, and knowledge of health workers. Key informant interviews and focus group discussions were organized to explore policies in terms of recruitment, training, and motivation. RESULTS: Zhejiang, Jilin, and Ningxia provinces had 0.33, 0.95, and 0.47 TB health professionals per 10 000 population respectively. They met the national staffing standard at the provincial level but with great variety at the county level. County-designated hospitals recruited TB health professionals from other departments of the same hospital, existing TB health professionals who used to work in CDC, and from township health centers. County-designated hospitals recruited new TB health professionals from three different sources: other departments of the same hospital, CDC, and township health centers. Most newly recruited professionals had limited competence and put on fixed posts to only provide outpatient services. TB doctors got 67/100 scores from a TB knowledge test, while public health doctors got 77/100. TB professionals had an average monthly income of 4587 RMB (667 USD). Although the designated hospital had special financial incentives to support, they still had lower income than other health professionals due to their limited capacity to generate revenue through service provision. CONCLUSIONS: The financing mechanism in designated hospitals and the job design need to be improved to provide sufficient incentive to attract qualified health professionals and motivate them to provide high-quality TB services.

Under-reporting of TB cases and associated factors: a case study in China.

BACKGROUND: Tuberculosis is a leading cause of death worldwide and has become a high global health priority. Accurate country level surveillance is critical to ending the pandemic. Effective routine reporting systems which track the course of the epidemic are vital in addressing TB. China, which has the third largest TB epidemic in the world and has developed a reporting system to help with the control and prevention of TB, this study examined its effectiveness in Eastern China. METHODS: The number of TB cases reported internally in two hospitals in Eastern China were compared to the number TB cases reported by these same hospitals in the national reporting systems in order to assess the accuracy of reporting. Qualitative data from interviews with key health officials and researcher experience using the TB reporting systems were used to identify factors affecting the accuracy of TB cases being reported in the national systems. RESULTS: This study found that over a quarter of TB cases recorded in the internal hospital records were not entered into the national TB reporting systems, leading to an under representation of national TB cases. Factors associated with underreporting included unqualified and overworked health personnel, poor supervision and accountability at local and national levels, and a complicated incohesive health information management system. CONCLUSIONS: This study demonstrates that TB in Eastern China is being underreported. Given that Eastern China is a developed province, one could assume similar problems may be found in other parts of China with fewer resources as well as many low- and middle-income countries. Having an accurate account of the number of national TB cases is essential to understanding the national and global burden of the disease and in managing TB prevention and control efforts. As such, factors associated with underreporting need to be addressed in order to reduce underreporting.

Inequity in healthcare needs, health service use and financial burden of medical expenditures in China: results from a consecutive household monitoring study in Jiangsu Province.

BACKGROUND: Although public medical insurance covers over 95% of the population in China, disparities in health service use and out-of-pocket (OOP) health expenditure across income groups are still widely observed. This study aims to investigate the socio-economic disparities in perceived healthcare needs, informal care, formal care and payment for healthcare and explore their equity implication. METHODS: We assessed healthcare needs, service use and payment in 400 households in rural and urban areas in Jiangsu, China, and included only the adult sample (N = 925). One baseline survey and 10 follow-up surveys were conducted during the 7-month monitoring period, and the Affordability Ladder Program (ALP) framework was adopted for data analysis. Negative binomial/zero-inflated negative binomial and logit regression models were used to explore factors associated with perceived needs of care and with the use of self-treatment, outpatient and inpatient care respectively. Two-part model and logit regression modeling were conducted to explore factors associated with OOP health expenditure and with the likelihood of incurring catastrophic health expenditure (CHE). RESULTS: After adjusting for covariates, rural residence was significantly associated with more perceived healthcare needs, more self-treatment, higher probability of using outpatient and inpatient service, more OOP health expenditure and higher likelihood of incurring catastrophic expenditure (P < 0.05). Compared to the Urban Employee Basic Medical Insurance (UEBMI), enrollment in the New Rural Cooperative Medical Scheme (NRCMS) or in the Urban Resident Basic Medical Insurance (URBMI) was correlated with lower probability of ever using outpatient services, but with more outpatient visits when people were at risk of using outpatient service (P < 0.05). NRCMS/URBMI enrollment was also associated with higher likelihood of incurring CHE compared to UEBMI enrollment (OR = 2.02, P < 0.05); in stratified analysis of the rural and urban sample this effect was only significant for the rural population. CONCLUSIONS: The rural population in Jiangsu perceived more healthcare needs, had a higher probability of using both informal and formal healthcare services, and had more OOP health expenditure and a higher likelihood of incurring CHE. The inequity mainly exists in health care financing, and may be partially addressed through improving the benefit packages of NRCMS/URBMI.

[Progress in genetic research on familiar aneurysms].

The subarachnoid hemorrhage (SAH) caused by ruptured intracranial aneurysms (IAs) is always a lethality. Increasing evidence suggests a familiar aggregation of IA occurrence, which may relate to genetics and there might be an increasing number of IAs in IA families when mutation of disease genes is aggregating. With the progress in the study of familiar intracranial aneurysms (FIAs), a large number of chromosome fragments are found to be related with IAs, such as 1p36, 5q31, 7q11, 14q22, 17cen, 19q13, Xp22. Further studies indicated that mutation of several genes could be the cause of FIAs, including TNFRSF13B, ANRIL, SOX17, ADAMTS15, RNF213 and LOXL2. The independent genetic epidemiologic study on aneurysm families can be used to discover the related genes more effectively, and to explore the mechanism of occurrence of IAs. It's also the precondition for the prevention of disease.

PIK3CA mutation sensitizes breast cancer cells to synergistic therapy of PI3K inhibition and AMPK activation.

Breast cancer has been emerging as a most common threat among women, thus many efforts were made to find drugs for fighting breast cancer. So far, PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) inhibitors have been believed to be effective drugs until frequent resistance emerged. Recently, PI3K H1047R mutation has been reported to sensitize breast cancer cells to PI3K inhibition by aspirin. Considering aspirin activates AMPK (AMP-activated protein kinase) simultaneously, it is possible that AMPK activators and PI3K inhibitors can synergistically inhibit breast cancers. Here we clearly observed synergistic suppression of cell growth in all three breast cancer cell lines (MCF-7, MDA-MB-361 and HCC38) when co-treating cells with PI3K inhibitor GDC-0941 and AMPK activator AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide). What is more, it is rather remarkable that the synergistic effect was much more dramatic in PIK3CA (PI3K catalytic subunit alpha) mutated (E545K) cells (MCF-7 and MDA-MB-361) than in PIK3CA wild-type cells (HCC38), which implied there is a relationship between PI3K genetic status and the efficacy of combination therapy. By using PIK3CA wild-type isogenic MCF-7 cell line, which exhibited attenuated cell proliferation compared with the parental MCF-7 cell line, we found endogenous reverse mutation of PIK3CA E545K alleles to wild-type sequence in MCF-7 cells dramatically impaired the synergy of PI3Ki&Ka (combinatorial PI3K inhibition and AMPK activation). Furthermore, PI3Ki&Ka significantly attenuated tumorigenesis of parental MCF-7 cells but not PIK3CA wild-type isogenic MCF-7 cells in tumor xenograft models. Taken together, our results suggest a promising precision therapy of PI3Ki&Ka in PIK3CA mutant breast cancers.

miR-25 promotes glioblastoma cell proliferation and invasion by directly targeting NEFL.

Glioblastoma multiforme (GBM) is the most malignant and common brain tumor; it is aggressive growth pattern means that GBM patients face a poor prognosis even when receiving the best available treatment modalities. In recent years, an increasing number of reports suggest that the discovery of microRNAs (miRNAs) might provide a novel therapeutic target for human cancers, including GBM. One miRNA in particular, microRNA-25 (miR-25), is overexpressed in several cancers, wherein accumulating evidence indicates that it functions as an oncogene. However, the function of miR-25 in GBM has not been totally elucidated. In this study, we demonstrated that miR-25 was significantly up-regulated in astrocytoma tissues and glioblastoma cell lines. In vitro studies further demonstrated that overexpressed miR-25 was able to promote, while its antisense oligos inhibited cell proliferation and invasion in U251 cells. Moreover, we identified neurofilament light polypeptide (NEFL) as a novel target molecule of miR-25. Also of note was the fact that NEFL was down-regulated with increased levels of miR-25 expression in human astrocytoma clinical specimens. In addition, via the mTOR signaling pathway, NEFL-siRNA could significantly attenuate the inhibitory effects of knockdown miR-25 on the proliferation and invasion of U251 cells. Overall, our results showed an important role for miR-25 in regulating NEFL expression in GBM, and suggest that miR-25 could be a potential target for GBM treatment.

[Microsurgical removal and prognostic analysis of petroclival meningiomas].

OBJECTIVE: To identify factors that predictive of quality of life after microsurgical removal of petroclival meningiomas. METHODS: A consecutive series of 71 cases of petroclival meningiomas received microsurgical removal between July 1991 and April 2010 were analyzed retrospectively. Quality of life was measured using Karnofsky performance scale (KPS). Complete pre-operative, post-operative and follow-up data were obtained from all 71 patients including 18 male and 53 female patients with the mean age of (47 ± 11) years (aging from 15 to 68 years). The duration between onset of symptoms and diagnosis ranged from 1 week to 180 months with the mean duration of (32 ± 30) months. And the tumor size was 15-72 mm with the average of (44 ± 11) mm. Main presentations included headache, unsteady gait, hemiparesis, dysphagia, hoarseness, facial numbness or pain, Bell's palsy, hearing impairment etc. The preoperative KPS was 40-100 with the average of 69 ± 11. The retrosigmoid (-transtentorial) approach was performed in most cases (91.5%). Intergroup χ² test and logistic regression analysis were conducted for prognostic factor characterization. RESULTS: The gross total resection (all were Simpson gradeII) reached in 48 cases (67.6%) and 1 case died postoperatively. The main new neurological dysfunctions were cranial nerve paralysis and hemiplegia with the postoperative KPS of 20-100 with the average of 73 ± 16.Sixty-four cases were followed for 4-132 months with the average of (61 ± 48) months. Seven patients died during follow-up, tumor recurrence and progression were identified in 6 and 8 cases, respectively. The KPS at the last visit ranged from 50 to 100 with the average of 83 ± 13. The extent of tumor resection (OR = 0.280, 95% CI: 0.081-0.967, P = 0.044), preoperative brainstem edema (OR = 0.100, 95% CI: 0.027-0.372, P = 0.001), relationships between tumor and neurovascular structures (OR = 0.288, 95% CI: 0.084-0.985, P = 0.047) and depth of invasion into cavernous sinus (OR = 0.254, 95% CI: 0.061-1.057, P = 0.048) had significant correlations with the prognostic quality of life. CONCLUSIONS: With regard of the choice of surgical approaches, the extent of tumor resection, the protection of neurovascular structures surrounding the tumor and the management of perioperative period, the therapeutic strategies for each patient should be customized to achieve better prognosis.

[Combined intervention of preconditioning and postconditioning against cerebral ischemia/reperfusion injury].

OBJECTIVE: To investigate the protective effect of combined ischemic preconditioning and postconditioning against cerebral ischemia/reperfusion (I/R) injury and the potential mechanism. METHODS: Sixty SD rats were randomized into a sham operation group, a brain I/R group (model group), a brain I/R plus preconditioning group (preconditioning group), a brain I/R plus postconditioning group (postconditioning group), and a brain I/R plus preconditioning and postconditioning group (combined intervention group). The rat brain I/R injury model was created by suture emboli method. Preconditioning was induced by 3 cycles of 15 s occlusion followed by 30 s recanalization of the middle cerebral artery twice respectively at 24 h and 1 h before model creation, and postconditioning was elicited by 3 cycles of 30 s reperfusion followed by 15 s ischemia before long time reperfusion. The rats were sacrificed at 48 h after the reperfusion. The cerebral infarct volume and oxidative stress parameters as well as p-Akt and p-ERK1/2 protein expressions in the brain tissues were determined. RESULTS: The cerebral infarct volumes showed no significant difference between the preconditioning group and the postconditioning group (P>0.05), but both were smaller than that in the model group and larger than that in the combined intervention group (all P values<0.01). In the model group, the level of oxidative stress was markedly increased (SOD activity increased and MDA level decreased), and both p-Akt and p-ERK1/2 protein expressions in the brain tissues were upregulated compared with those in the sham group (all P<0.01). Compared with the model group, the oxidative stress parameters presented no evident difference in preconditioning group (P>0.05), but p-Akt expression was slightly upregulated and p-ERK1/2 was remarkably down-regulated (P<0.05 and P<0.01) In the postconditioning group, the level of oxidative stress was significantly decreased, and p-Akt expression was dramatically increased with a mild down-regulation of p-ERK1/2 expression (P<0.01 and P<0.05). In the combined intervention group, the oxidative stress decrease the p-Akt expression rise and p-ERK1/2 expression inhibition were significantly greater than those in either the preconditioning group or the postconditioning group (all P values<0.01). CONCLUSION: Combined treatment of preconditioning and postconditioning exerts stronger protective effect against cerebral I/R injury than either preconditioning or postconditioning alone. The mechanism is possibly due to the different but complementary protection of preconditioning and postconditioning against I/R injury.