TAK1 is an essential kinase for STING trafficking.

The translocation of stimulator of interferon genes (STING) from the endoplasmic reticulum (ER) to the ER-Golgi intermediate compartment (ERGIC) enables its activation. However, the mechanism underlying the regulation of STING exit from the ER remains elusive. Here, we found that STING induces the activation of transforming growth factor beta-activated kinase 1 (TAK1) prior to STING trafficking in a TAK1 binding protein 1 (TAB1)-dependent manner. Intriguingly, activated TAK1 directly mediates STING phosphorylation on serine 355, which facilitates its interaction with STING ER exit protein (STEEP) and thereby promotes its oligomerization and translocation to the ERGIC for subsequent activation. Importantly, activation of TAK1 by monophosphoryl lipid A, a TLR4 agonist, boosts cGAMP-induced antitumor immunity dependent on STING phosphorylation in a mouse allograft tumor model. Taken together, TAK1 was identified as a checkpoint for STING activation by promoting its trafficking, providing a basis for combinatory tumor immunotherapy and intervention in STING-related diseases.

Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS.

Virus infection modulates both host immunity and host genomic stability. Poly(ADP-ribose) polymerase 1 (PARP1) is a key nuclear sensor of DNA damage, which maintains genomic integrity, and the successful application of PARP1 inhibitors for clinical anti-cancer therapy has lasted for decades. However, precisely how PARP1 gains access to cytoplasm and regulates antiviral immunity remains unknown. Here, we report that DNA virus induces a reactive nitrogen species (RNS)-dependent DNA damage and activates DNA-dependent protein kinase (DNA-PK). Activated DNA-PK phosphorylates PARP1 on Thr594, thus facilitating the cytoplasmic translocation of PARP1 to inhibit the antiviral immunity both in vitro and in vivo. Mechanistically, cytoplasmic PARP1 interacts with and directly PARylates cyclic GMP-AMP synthase (cGAS) on Asp191 to inhibit its DNA-binding ability. Together, our findings uncover an essential role of PARP1 in linking virus-induced genome instability with inhibition of host immunity, which is of relevance to cancer, autoinflammation, and other diseases.

Decreased Expression of the Host Long-Noncoding RNA-GM Facilitates Viral Escape by Inhibiting the Kinase activity TBK1 via S-glutathionylation.

Viruses have evolved multiple strategies to evade elimination by the immune system. Here we examined the contribution of host long noncoding RNAs (lncRNAs) in viral immune evasion. By functional screening of lncRNAs whose expression decreased upon viral infection of macrophages, we identified a lncRNA (lncRNA-GM, Gene Symbol: AK189470.1) that promoted type I interferon (IFN-I) production and inhibited viral replication. Deficiency of lncRNA-GM in mice increased susceptibility to viral infection and impaired IFN-I production. Mechanistically, lncRNA-GM bound to glutathione S-transferase M1 (GSTM1) and blocked GSTM1 interaction with the kinase TBK1, reducing GSTM1-mediated S-glutathionylation of TBK1. Decreased S-glutathionylation enhanced TBK1 activity and downstream production of antiviral mediators. Viral infection reprogrammed intracellular glutathione metabolism and furthermore, an oxidized glutathione mimetic could inhibit TBK1 activity and promote viral replication. Our findings reveal regulation of TBK1 by S-glutathionylation and provide insight into the viral mediated metabolic changes that impact innate immunity and viral evasion.

Adult Connective Tissue-Resident Mast Cells Originate from Late Erythro-Myeloid Progenitors.

Tissue-resident mast cells are associated with many inflammatory and physiological processes. Although mast cells arise from the yolk sac, the exact ontogeny of adult mast cells remains unclear. Here we have investigated the hematopoietic origin of mast cells using fate-mapping systems. We have shown that early erythro-myeloid progenitors (EMPs), late EMPs, and definitive hematopoietic stem cells (HSCs) each gave rise to mast cells in succession via an intermediate integrin ß7+ progenitor. From late embryogenesis to adult, early EMP-derived mast cells were largely replaced by late EMP-derived cells in most connective tissues except adipose and pleural cavity. Thus, mast cells with distinct origin displayed tissue-location preferences: early EMP-derived cells were limited to adipose and pleural cavity and late EMP-derived cells dominated most connective tissues, while HSC-derived cells were a main group in mucosa. Therefore, embryonic origin shapes the heterogeneity of adult mast cells, with diverse functions in immunity and development.

A non-canonical role of endothelin converting enzyme 1 (ECE1) in promoting lung cancer development via directly targeting protein kinase B (AKT).

BACKGROUND: Lung cancer is the second most common malignancy in the world, and lung adenocarcinoma (LUAD) in particular is the leading cause of cancer death worldwide. Endothelin converting enzyme 1 (ECE1) is a membrane-bound metalloprotease involved in endothelin-1 (ET-1) processing and regulates vasoconstriction. However, very few studies have reported the involvement of ECE1 in regulating tumor cell proliferation, and the mechanism remains poorly understood. Therefore, we aimed to determine the role of ECE1 in lung cancer development. METHODS: The Cancer Genome Atlas database and Kaplan-Meier plotter were used to assess the association between ECE1 and lung cancer. The expression of ECE1 was detected using immunohistochemistry staining and western blotting. A variety of in vitro assays were performed to evaluate the effects of ECE1 on the colony formation, proliferation, migration and invasion using ECE1 knockdown lung cancer cells. The gene expression profiles regulated by ECE1 were investigated by RNA sequencing. An immunoprecipitation assay and immunofluorescence assay were used to evaluate the mechanism underlying the regulatory effect of ECE1 on protein kinase B (AKT). The effect of ECE1 on tumor development was assessed by xenografted lung cancer cells in either C57BL/6 mice or nude mice. RESULTS: ECE1 was upregulated in LUAD and correlated with the poor prognosis of patients with LUAD. Functional studies showed that knockdown of ECE1 retarded the progression of tumors formed by lung cancer cells at least partly by inhibiting tumor cell proliferation. Moreover, ECE1 accelerated tumor cell proliferation through promoting AKT activation dispensable of its canonical target ET-1. Mechanically, ECE1 interacted with the pleckstrin homology (PH) domain of AKT and facilitated its translocation to the plasma membrane for activation. Furthermore, the inhibition of AKT activity counteracted the lung cancer cell growth inhibition observed both in vitro and in xenografts caused by ECE1 suppression. CONCLUSIONS: The present study reveals a non-canonical function of ECE1 in regulating AKT activation and cell proliferation, which provides the basis for the development of a novel strategy for the intervention of cancer including LUAD by abrogating ECE1-AKT signaling.

CDK inhibitor Palbociclib targets STING to alleviate autoinflammation.

Aberrant activation of stimulator of interferon genes (STING) is tightly associated with multiple types of disease, including cancer, infection, and autoimmune diseases. However, the development of STING modulators for the therapy of STING-related diseases is still an unmet clinical need. We employed a high-throughput screening approach based on the interaction of small-molecule chemical compounds with recombinant STING protein to identify functional STING modulators. Intriguingly, the cyclin-dependent protein kinase (CDK) inhibitor Palbociclib was found to directly bind STING and inhibit its activation in both mouse and human cells. Mechanistically, Palbociclib targets Y167 of STING to block its dimerization, its binding with cyclic dinucleotides, and its trafficking. Importantly, Palbociclib alleviates autoimmune disease features induced by dextran sulphate sodium or genetic ablation of three prime repair exonuclease 1 (Trex1) in mice in a STING-dependent manner. Our work identifies Palbociclib as a novel pharmacological inhibitor of STING that abrogates its homodimerization and provides a basis for the fast repurposing of this Food and Drug Administration-approved drug for the therapy of autoinflammatory diseases.

Migration experiences and reported commercial and non-commercial sexual behaviors among newly diagnosed HIV infections in China: a cross-sectional study.

BACKGROUND: Migration is known to influence human health. China has a high migration rate and a significant number of people who are HIV-positive, but little is known about how these factors intersect in sexual risk behaviors. OBJECTIVE: This study aimed to explore sexual risk behaviors between migrants and non-migrants among newly diagnosed HIV infections, and assess the changes of sexual risk behaviors with length of stay in the current city of migrants. METHODS: A cross-sectional questionnaire was conducted among people newly diagnosed with HIV from July 2018 to December 2020 who lived in Zhejiang Province. In the study, sexual risk behaviors included having multiple sexual partners and unprotected sexual behaviors (in commercial sexual behaviors, non-commercial sexual behaviors, heterosexual behaviors, and homosexual behaviors). Binary logistic regression models were employed to explore the influencing factors of sexual risk behaviors, measured by multiple sexual partners and unprotected sexual partners. RESULTS: A total of 836 people newly diagnosed with HIV/AIDS were incorporated in the study and 65.31% (546) were migrants. The percentages of non-commercial sexual behaviors among migrants were statistically higher than those of non-migrants. Commercial heterosexual behavior was higher among non-migrants compared with migrants. The proportion of study participants having unprotected sexual behaviors and multiple sexual partners with commercial/non-commercial partners was both higher among migrants compared with non-migrants. Among migrants, the likelihood of sexual risk behaviors in both commercial and non-commercial sex increased in the first 3 years and reduced after 10 years. Compared with non-migrants, migrants were statistically associated with multiple sexual partners [P = .007, odds ratio (OR) = 1.942]. However, migrants did not exhibit a significant difference in unprotected sexual behaviors compared with non-migrants. In addition, migrants aged between 18 and 45 years who relocated to the current city in the past 2-3 years tended to have multiple sexual partners (P < .05). CONCLUSIONS: People newly diagnosed with HIV engaged in different sexual risk behaviors among migrants and non-migrants and more attention should be paid to migrants. For non-migrants, it is urgent to promote the prevention of commercial sexual behaviors. For migrants, prevention of non-commercial sexual behaviors and universal access to health care especially for new arrivals who migrated to the current city for 2-3 years are needed. Moreover, sexual health education and early HIV diagnosis are necessary for the entire population.

Polo-like Kinase 4: the Variation During Therapy and its Relation to Treatment Response and Prognostic Risk Stratification in Childhood Acute Lymphoblastic Leukemia Patients.

Polo-like kinase 4 (PLK4) plays an essential role in the tumorigenesis of some blood malignancies; consequently, we hypothesized that PLK4 might serve as a potential biomarker in childhood acute lymphoblastic leukemia (ALL) patients. Therefore, this study investigated the expression of PLK4 and its clinical relevance in childhood ALL patients. Bone marrow specimens were collected from 95 childhood ALL patients and 20 primary immune thrombocytopenia patients (as controls), and their PLK4 expression (reverse transcription-quantitative polymerase chain reaction) was measured after enrollment. Besides, the PLK4 expression in childhood ALL patients was also determined at day 15 after the initiation of induction therapy (D15). PLK4 was increased in childhood ALL patients compared with controls (2.830 (interquartile range (IQR): 1.890-3.660) versus 0.976 (IQR: 0.670-1.288), P ≤0.001). PLK4 at diagnosis was elevated in T cell acute lymphoblastic leukemia patients than in B cell acute lymphoblastic leukemia patients ( P =0.027). Besides, PLK4 at diagnosis was positively linked with the Chinese Medical Association risk stratification ( P =0.016), but not with prednisone response ( P =0.077) or bone marrow response ( P =0.083). In addition, PLK4 was decreased at D15 after treatment compared with at diagnosis ( P ≤0.001). Interestingly, PLK4 at D15 (P=0.033) was elevated in T cell acute lymphoblastic leukemia patients than in B cell acute lymphoblastic leukemia patients. Furthermore, increased PLK4 at D15 was associated with poor prednisone response ( P =0.018), poor bone marrow response ( P =0.034), and increased the Chinese Medical Association risk stratification ( P =0.015). In terms of prognosis, high PLK4 was associated with shorter event-free survival ( P =0.020), whereas it was not related to the overall survival ( P =0.135). In conclusion, PLK4 has the potential as a biomarker for treatment response and prognostic risk stratification of childhood ALL patients.

Sexual orientation and quality of life of people living with HIV/AIDS in China: evidence from an institutional-based cross-sectional study.

BACKGROUND: At the end of 2019, there were approximately one million people known to be living with HIV/AIDS (PLWHA) in China. Different sexual orientation groups were observed within the people living with HIV in general, and studies have found that socially marginalized groups exist among this population, such as men who have sex with men (MSM) and bisexual individuals. Correspondingly, sexual orientation may pose challenges to the emotional and psychological development of PLWHA. Under this background, we aim to analyze whether sexual orientation affects the health-related quality of life (HRQOL) of PLWHA in order to provide evidence and suggestions for how wellbeing can be enhanced for sexual minorities living with HIV/AIDS. METHOD: An institutional-based cross-sectional study design was used to collect data from PLWHA in Yunnan province and Beijing municipality in China. In our study, sexual orientation was classified as heterosexual, homosexual and bisexual, and HRQOL was measured using the Chinese WHOQOL-HIV-BREF scale. Logistic regression model was used to analyze the relationships of participants' sexual orientation and HRQOL. In addition, multivariable stepwise liner regression model was used to analyze the factors influencing HRQOL of PLWHA. RESULTS: In total, 2610 PLWHA were included in the study, 36.5% of the participants identified as homosexual and most were males, 13.8% were bisexuals and 49.7% were heterosexuals. For the overall HRQOL, the homosexual PLWHA group scored highest (81.53 ± 12.45) with a high HRQOL score signifying a better health-related quality of life, followed by bisexuals (79.72 ± 12.81) and heterosexuals (78.02 ± 13.06). However, the bisexual group showed a markedly higher level of spiritual health. In addition, there was no statistical difference in the total HRQOL scores and domains by sex roles among the homosexual group (p > 0.01). However, sexual orientation was statistically associated with the physical and spiritual domains of HRQOL (p < 0.05). CONCLUSION: In terms of sexual orientation for those living with HIV/AIDS, a better quality of life was found for homosexual individuals, whilst being a heterosexual individual saw a negative impact on quality of life, especially in the physical and spiritual domains. Strengthening the individualized and comprehensive care for heterosexual group as well as other sexual minority populations is imperative. Moreover, heterosexual PLWHA are more likely to be ignored and require more support and care to improve their HRQOL than do those in sexual minorities.

Family planning knowledge, attitude and practice among Rohingya women living in refugee camps in Bangladesh: a cross-sectional study.

BACKGROUND: Considering the high risk of maternal morbidity and mortality, increased risks of unintended pregnancy, and the unmet need for contraceptives prevalent among the Rohingya refugees, this study aims to explore the knowledge, attitude, and practice (KAP) of family planning (FP) and associated factors among Rohingya women living in refugee camps in Bangladesh. METHODS: Four hundred Rohingya women were interviewed. Data were collected using a structured and pretested questionnaire, which included study participants' socio-demographic characteristics, access to FP services, knowledge, attitude, and practice of FP. Linear regression analysis was performed to identify the influencing factors of FP-KAP. RESULTS: Of the 400 Rohingya refugee women, 60% were unaware that there was no physical harm brought by using a permanent method of birth control. Half of the women lack proper knowledge regarding whether a girl was eligible for marriage before the age of 18. More than two-thirds of the women thought family planning methods should not be used without the husband's permission. Moreover, 40% were ashamed and afraid to discuss family planning matters with their husbands. Of the study participants, 58% had the opinion that a couple should continue bearing children until a son is born. Linear regression analyses found that study participants' who have a profession, have less children, whose primary source of FP knowledge was through a physician/nurse, have had FP interventions in the camp, and talk with a health care provider on FP were found to have better FP-KAP. CONCLUSION: The study showed that Rohingya refugee women are a marginalized population in terms of family planning and their comprehensive FP-KAP capability was low. Contraceptives among the Rohingyas were unpopular, mainly due to a lack of educational qualifications and family planning awareness. In addition, family planning initiatives among Rohingya refugees were limited by a conservative culture and religious beliefs. Therefore, strengthening FP interventions and increasing the accessibility to essential health services and education are indispensable to improving improve maternal health among Rohingya refugees.

Considering the high risk of maternal morbidity and mortality, increased risks of unintended pregnancy, and the unmet need for contraceptives prevalent among the Rohingya refugees, this study aims to explore the knowledge, attitude and practice (KAP) of family planning (FP) and associated factors among Rohingya women living in the refugee camps in Cox's Bazar, Bangladesh. Four hundred Rohingya women participated in the study. We found that Rohingya refugee women were a marginalized population in family planning and their comprehensive FP-KAP status was low. Contraceptive uptake among the Rohingya women was low due to a lack of education and family planning awareness. In addition, family planning initiatives among Rohingya refugees were limited by various traditional cultural and religious beliefs. Therefore, strengthening FP interventions and increasing accessibility to essential health services and education are indispensable to improving maternal health among refugees.

Disparity in physician-patient communication by ethnicity: evidence from Bangladesh.

BACKGROUND: Physician-patient communication behavior (PPCB) is the primary process by which medical decision-making occurs and health outcome depends. Physician-patient communication differences may partly from the ethnic disparities. To examine this problem, this study aims to explore whether physician-patient communication differs by ethnicity during primary care medical consultations. METHODS: The study was conducted among the Bengali and ethnic minority patients (N = 850) who visited a physician for medical consultations. Data were collected using a structured post-consultation questionnaire. T-test was conducted to compare the communication between the Bengali and ethnic minority patients. Multiple linear regression analyses were performed to identify the factors associated with favorable communication behavior from the physicians. RESULTS: Bengali patients received more supportive communication behaviors from the Bengali doctors than that of ethnic minority patients including physicians' cheerful greetings, encouraging patients to express health problems and asking questions, listening carefully, responding to questions and concerns, explaining to patients about medical examination procedures, medication, probable side effects, discussing treatment options, involved the patients in decisions, and spending adequate time. Results of linear regression showed that respondents' level of education, internet use, knowledge about the health issue, having a pre-organized plan about the content of medical consultation, information seeking about the health problem, visiting female doctors, and a quiet ambience of the doctor's room are significantly associated with a better PPCB score for the Bengali patients. In contrast, age, being the resident of an urban area, perception of affecting a minor health problem, having a pre-organized plan about the content of medical consultation, patients' involvement in physicians' decision-making about the treatment, and talking time resulted in better physician-patient communication for the ethnic minority patients. CONCLUSION: This study suggests that reducing disparity in the socio-economic status of the ethnic minority groups through development programs and educating healthcare providers on how to use patient-centered communication skills to engage with their patients is one solution to improve equity in the delivery of healthcare and ensure than patients are receiving high-quality treatment, no matter their race or ethnicity.

A retrospective analysis of hospital treatment expenditures among young and middle age patients with cancer, 2013-2017 under health reform.

Under 60 year olds represent a rapidly growing segment of the cancer population. They often face longer hospital stays, higher treatment intensity, and hospitalization costs. In this background, we aim to assess the impact of the 2009 reforms on the hospital expenses of younger cancer inpatients. Our study sample included 11 791 young and middle age stomach, lung, colorectal, esophageal, and breast cancer inpatients hospitalized during 2013 to 2017. Hospitalization treatment costs of under 60 cancer inpatients increased, but it fell in 2017 under the impact of the health reforms. However, out-of-pocket expenditures rose, which partly reflected the failure of the health insurance scheme to adequately cover cancer inpatient cost, potentially imposing financial hardships on cancer inpatients and their families. To continue to reduce the economic burden of cancer patients, early screening and diagnosis among younger populations and enhanced hospice care integrated with the ongoing primary health care reform are important.

Reproductive health communication between mother and adolescent daughter in Bangladesh: a cross-sectional study.

BACKGROUND: Parent-adolescent reproductive health (RH) communication is one of the potential sources of information for adolescents on the topic. Given that female adolescents in Bangladesh are faced with increasing RH-related risks, it is important to understand how parents communicate about RH to their adolescents from the adolescents' perspectives. Therefore, the aim of this study is to explore the status of mother-adolescent daughter communication on reproductive health in Bangladesh. METHODS: A cross-sectional study targeting female students was conducted in five high schools in Chittagong based on a self-administered questionnaire survey. A description method was used to describe the characteristics of mother-adolescent daughters' communication on RH including the frequency, type and the quantity of topics. Bivariate and multivariate logistic regression analyses were performed to explore the factors influencing mother-adolescent daughter communication. RESULTS: In the study, 1174 female students aged from 13 to 19 years old were included. The main source of knowledge on RH was from their mother (62%), and the mother was the person who communicated first on RH with adolescent students. The topics of mother-daughter communication were mainly focused on menstruation issues (> 80%). Multivariate logistic regressions showed that Hindu students, students with good RH knowledge, adolescents' mothers having good RH knowledge, mothers with high media use, good mother-daughter relationship, daughters' regular general communication with mothers, and students' perceiving comfort in RH communication with their mothers were reported as significant predictors for a good RH communication status. On the contrary, students having family members numbering more than four, whose primary source of reproductive health information was friends/classmates as well as media were less likely to have better RH communication with mothers. CONCLUSIONS: The overall communication on reproductive health between adolescent daughters and their mothers was not good. This study suggests for conducting qualitative research investigating the socio-cultural context within which the RH communications happen. and how to address the obstacles that might hinder this communication.

The economic burden of dementia in China, 1990-2030: implications for health policy.

OBJECTIVE: To quantify and predict the economic burden of dementia in China for the periods 1990-2010 and 2020-2030, respectively, and discuss the potential implications for national public health policy. METHODS: Using a societal, prevalence-based, gross cost-of-illness approach and data from multiple sources, we estimated or predicted total annual economic costs of dementia in China. We included direct medical costs in outpatient and inpatient settings, direct non-medical costs - e.g. the costs of transportation - and indirect costs due to loss of productivity. We excluded comorbidity-related costs. FINDINGS: The estimated total annual costs of dementia in China increased from 0.9 billion United States dollars (US$) in 1990 to US$ 47.2 billion in 2010 and were predicted to reach US$ 69.0 billion in 2020 and US$ 114.2 billion in 2030. The costs of informal care accounted for 94.4%, 92.9% and 81.3% of the total estimated costs in 1990, 2000 and 2010, respectively. In China, population ageing and the increasing prevalence of dementia were the main drivers for the increasing predicted costs of dementia between 2010 and 2020, and population ageing was the major factor contributing to the growth of dementia costs between 2020 and 2030. CONCLUSION: In China, demographic and epidemiological transitions have driven the growth observed in the economic costs of dementia since the 1990s. If the future costs of dementia are to be reduced, China needs a nationwide dementia action plan to develop an integrated health and social care system and to promote primary and secondary prevention.

[Analysis of schistosomiasis prevalence in endemic areas using retrospective space-time permutation scan statistics].

Objective: To analyze the characteristics of schistosomasis prevalence by using the spatial epidemiological method, and test the application of retrospective space-time permutation scan statistics in determining mountainous and lake-type endemic areas of schistosomiasis. Methods: The data of schistosomasis in humans, cattle and snails in Jiangxi Province during 2009-2014 and in Yunnan Province during 2004-2013 were collected and analyzed. The temporal and spatial distribution of schistosomiasis endemic areas in the two provinces was analyzed with retrospective space-time permutation scan statistics. Results: The prevalence of schistosomiasis in residents and Oncomelania snails showed a trend of decline in Jiangxi, from 0.21% and 0.03% in 2009 to 0.01% and zero in 2014. A similar trend was found in cattle, from 1.25% in 2012 to 0.12% in 2014. The average annual percentage change (APC) in residents was-47.36%(P < 0.05). The space-time permutation clustering analysis revealed a temporal and spatial clustering of schistosomiasis prevalence from 2009 to 2014 in residents, cattle, and snails, with 3,2 and 1 clustering areas, respectively, all distributed in Poyang Lake Region. A similar declining trend of schistosomiasis prevalence was found in residents, snails and cattle in Yunnan during 2004-2013, from 2.49%,0.70% and 3.76% in 2004 to no infection in residents and snails and 0.02% in cattle in 2013. The APC in residents was-49.17%(P < 0.05). There was a temporal and spatial clustering of schistosomiasis prevalence during 2004-2013 in residents, cattle, and snails, with 2,2 and 6 clustering areas, respectively. Conclusion: A declining trend of schistosomiasis prevalence is shown in lake-type endemic areas in Jiangxi during 2009-2014 and in mountainous endemic areas in Yunnan during 2004-2013. The retrospective space-time permutation scan statistics reveal a clustering of schistosomiasis in humans, cattle, and snails, suggesting its applicability in analyzing the temporal and spatial distribution of schistosomiasis.

IFN-γ primes macrophage activation by increasing phosphatase and tensin homolog via downregulation of miR-3473b.

The classical activation of macrophages, one of major innate effector cells, requires IFN-γ pretreatment (priming) and subsequent TLR stimuli (triggering). The priming effect of IFN-γ can promote macrophages to secrete higher level of proinflammatory cytokines but lower level of the anti-inflammatory cytokines, enhancing microbicidal and tumoricidal activity of macrophages. However, the underlying molecular mechanisms for IFN-γ-priming effect on macrophage activation remain to be fully understood. microRNAs (miRNAs) are now emerging as important regulators in immune response, including signaling transduction in immune cell function. In this study, we explored the effect of IFN-γ on miRNA expression profiling in macrophages and tried to identify the definite miRNA involved in the priming effect of IFN-γ. We discovered that miR-3473b, which was significantly downregulated after IFN-γ priming, could attenuate the priming effect of IFN-γ. miR-3473b promoted Akt/glycogen synthase kinase 3 signaling and IL-10 production through directly targeting phosphatase and tensin homolog (PTEN) to suppress activation of macrophages and inflammatory response. Our data indicate that IFN-γ beefs up macrophage innate response and cytotoxicity by downregulating miR-3473b to release PTEN from suppression, and then the increase of PTEN contributes to the full activation of IFN-γ-primed macrophages. Our results provide mechanistic insight to priming effect of IFN-γ on macrophage classical activation by identifying an IFN-γ/miR-3473b/PTEN regulatory loop in the regulation of macrophage function.

The economic burden of mental disorders in China, 2005-2013: implications for health policy.

BACKGROUND: Mental disorders represent a major contributor to disease burden worldwide. We sought to quantify the national economic burden of mental disorders in China. METHODS: We used a prevalence-based, bottom-up approach to estimate the economic costs of mental disorders in 2005-2013 in China. Prevalence data were derived from a national survey. Cost data were derived from the electronic health records of two psychiatric hospitals that consisted of 25,289 outpatients (10%) and inpatients (90%) who were diagnosed with a mental disorder. Cost items included direct medical costs, direct non-medical costs, and indirect costs. RESULTS: The total annual costs of mental disorders in China increased from $1,094.8 in 2005 to $3,665.4 in 2013 for individual patients, and from $21.0 billion to $88.8 billion for the whole society. The total costs of mental disorders in 2013 accounted for more than 15% of the total health expenditure in China, and 1.1% of China's gross domestic product. If the needs of the professional care for all patients with mental illnesses were fully met, the potential economic costs would have been almost five times higher than the actual estimated costs. CONCLUSIONS: Mental disorders imposed a huge economic burden on individuals and the society in China. A nation-wide strategic action plan for preventing mental disorders and promoting mental health and well-being is in urgent need to reduce the individual and societal costs of mental illnesses.

Randomized, controlled pharmacokinetic and pharmacodynamic evaluation of albinterferon in patients with chronic hepatitis B infection.

BACKGROUND AND AIMS: Albinterferon is a fusion of albumin and interferon-α2b developed to improve the pharmacokinetics, convenience, and potential efficacy of interferon-α for the treatment of chronic hepatitis infections. METHODS: This open-label, randomized, active-controlled, multicenter study investigated the safety and efficacy of albinterferon in patients with chronic hepatitis B virus (HBV) infection who were e-antigen (HBeAg) positive. One hundred and forty-one patients received one of four albinterferon doses/regimens or pegylated-interferon-α2a. Primary efficacy outcomes were changes in serum HBeAg and antibody, HBV-DNA, and alanine aminotransferase. Principal safety outcomes were changes in laboratory values, pulmonary function, and adverse events. RESULTS: The study was prematurely terminated as phase III trials in hepatitis C infection indicated noninferior efficacy but inferior safety compared with pegylated-interferon-α2a. Here, all treatment groups had a significant reduction in HBV-DNA from baseline. Reductions in HBV-DNA were not significantly different, except the 1200 µg every 4 weeks albinterferon dose which was inferior compared with pegylated-interferon-α2a. The serum alanine aminotransferase levels decreased in all arms. The per-patient incidence of adverse events was not significantly different for albinterferon (96.4-100%) and pegylated-interferon-α2a (93.1%). Total adverse events, however, were higher for albinterferon and correlated to dose. Decreased lung function was found in all arms (∼93% of patients), and was more common in some albinterferon groups. CONCLUSIONS: Albinterferon doses with similar anti-HBV efficacy to pegylated-interferon-α2a had higher rates of certain adverse events, particularly changes in lung diffusion capacity (http://www.clinicaltrials.gov number NCT00964665).

Mental health inpatient treatment expenditure trends in China, 2005-2012: evidence from Shandong.

BACKGROUND: Mental health is increasingly becoming a huge public health issue in China. Yet for various cultural, healthcare system, and social economic reasons, people with mental health need have long been under-served in China. In order to inform the current on-going health care reform, empirical evidences on the economic burden of mental illnesses in China are urgently needed to contribute to health policy makers' understanding of the potential benefits to society from allocating more resources to preventing and treating mental illness. However, the cost of mental illnesses and particularly its trend in China remains largely unknown. AIMS OF THE STUDY: To investigate the trend of health care resource utilization among inpatients with mental illnesses in China, and to analyze what are the factors influencing the inpatient costs. METHOD: Our study sample included 15,721 patients, both adults and children, who were hospitalized over an eight-year period (2005-2012) in Shandong Center for Mental Health (SCMH), the only provincial psychiatric hospital in Shandong province, China. Data were extracted from the Health Information System (HIS) at SCMH, with detailed and itemized cost data on all inpatient expenses incurred during hospitalization. The identification of the patients was based on the ICD-10 diagnoses recorded in the HIS. Descriptive analysis was done to analyze the trend of hospitalization cost and length of stay during the study period. Multivariate stepwise regression analysis was conducted to assess the factors that influence hospitalization cost. RESULTS: Among the inpatients in our sample, the most common mental disorders were schizophrenia, schizotypal and delusional disorders. The disease which had the highest per capita hospital expense was behavioral and emotional disorders with onset usually occurring in childhood and adolescence (RMB 8,828.4; US$ 1,419.4, as compared to the average reported household annual income of US$ 2,095.3 in China). The average annual growth rate of per capita hospitalization cost was 23.6%, with the inpatient cost reaching RMB 11,949 (US$ 1921.1) in 2012. The hospitalization cost was found to be strongly associated with hospital length of stay, level of care, age, employment status, admission diagnoses, and frequency of hospitalization. DISCUSSION: Our study found that mental health inpatient resources use, particularly hospitalization cost, has been growing at an increasing rate. In our sample, hospitalization cost nearly tripled from 2005 to 2012. Mental illnesses and the related economic burden on the population will continue to grow, making mental health a major public health issue in China. Hospital length of stay was found to be increasing in our sample, and positively correlated with hospitalization cost. Childhood and adolescence behavioral and emotional disorders were found to be significantly associated with higher inpatient cost. IMPLICATIONS FOR HEALTH POLICIES AND FUTURE RESEARCH: The policy implications generated from the results of this study are two-fold: first of all, in order to meet the growing need of mental health care in China, the government needs to significantly increase its spending in preventing and treating mental illnesses. Second, cost containment in inpatient care would become a major challenge for mental health policy makers in China. Government support, clinical practices and guideline development, as well as research are urgently needed to promote mental health prevention and improve the efficiency of mental health system in China. The current mental health system, like the overall healthcare system in China, relies heavily on hospital inpatient care. In order to build a sustainable mental health care system to meet increasing population need in China, it is crucial to integrate mental health care reform with the ongoing primary health care reform. Future mental health policy reform and research in China should put more focus on how to strengthen primary care system as well as community support, establish effective two-tier referring mechanism between hospital and primary care system, and to ensure continuity of care.

[Risk assessment for malaria elimination in P. R. China].

OBJECTIVE: To identify the risk area in China during the malaria elimination process, and provide the evidence for promotion of the national malaria elimination programme and implementation of elimination strategy. METHODS: Data collection was conducted in 24 endemic provinces in 2010, including data of transmission capacity, potential risk of malaria transmission and the capacity of health professional team at county level. Quantitative assessment of the malaria transmission risk as well as the capacity of health facilities were conducted based on the calculation of malaria transmission risk index (MTI) and health facilities capacity index (CI). ArcGIS 10.0 was used to develop the risk map based on the outcome of quantitative assessment. RESULTS: The data of transmission capacity, potential risk of transmission and the capacity of health professional team were collected from 2147 counties in 24 provinces. Based on MTI and CI calculated for each county, statistic results showed that about 40% of the counties were under the average level of both MTI and CI. The relationship among potential risk of transmission, the capacity of health professional team and malaria incidence were analyzed in three dimensions, and four types were categorized among 2147 counties. Type I (super-high risk area) counties (20) distributed in Yunnan (9), Guangxi (5), Henan (1), Hunan (1), Hebei (1), Sichuan (1), Chongqing (1), and Tibet (1). 17 counties were classified into type II (high risk area) area, distributed in Yunnan (3), Guangxi (2), Guizhou (2), Shaanxi (2), Guangdong (1), Jiangxi (1), Hubei (1), Sichuan (1), Gansu (1), Hebei (1), Fujian (1) and Tibet (1). A total of 170 type III (moderate risk area) counties distributed in 19 provinces including Yunnan (15), Guizhou (14), Hebei (14), Sichuan (13), Shanxi (10), Guangxi (9), Hunan (9), Anhui (9), Jiangsu (9), Shaanxi (9), Shandong (9), Chongqing (8), Gansu (8), Jiangxi (7), Henan (7), Fujian (6), Guangdong (5), Hubei (5), and Zhejiang (4). 1940 type IV (low risk area) counties distributed in 24 provinces. CONCLUSION: The distribution of four types of risk area for malaria elimination is identified in China.