Efficacy of epidural esketamine on postoperative sleep quality after laparoscopic and robotic lower abdominal surgeries: a study protocol for randomised, double-blind, controlled trial.

INTRODUCTION: Postoperative sleep disturbances significantly impair postoperative recovery. The administration of intravenous esketamine has been shown to potentially improve postoperative sleep quality. However, the effectiveness of epidural esketamine in improving postoperative sleep quality remains to be elucidated. This study aims to explore the impact of both intraoperative and postoperative use of epidural esketamine on the postoperative sleep quality of patients undergoing minimally invasive lower abdominal surgeries. METHODS AND ANALYSIS: This randomised, double-blind, parallel-group, placebo-controlled trial will be conducted at the Fudan University Shanghai Cancer Centre. A total of 128 adults undergoing minimally invasive lower abdominal surgeries will be randomly allocated in a 1:1 ratio to either the esketamine group or the placebo group. In the esketamine group, epidural esketamine will be administered intraoperatively (0.2 mg/kg) and postoperatively (25 mg). Postoperatively, all patients will receive epidural analgesia. The primary outcome of the study is the incidence of poor sleep quality on the third day after surgery. The sleep quality assessment will be conducted using the Pittsburgh Sleep Quality Index and a Numeric Rating Scale of sleep. The main secondary outcomes include postoperative pain and anxiety and depression scores. The postoperative pain, both rest pain and movement pain, will be assessed using a Numerical Rating Scale within 5 days after surgery. Anxiety and depression scores will be evaluated using the Hospital Anxiety and Depression Scale both before and after the surgery. Safety outcomes will include delirium, fidgeting, hallucinations, dizziness and nightmares. The analyses will be performed in accordance with intention-to-treat principle ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Ethics Committee of the Shanghai Cancer Centre (2309281-9). Prior to participation, all patients will provide written informed consent. The results of the trial are intended to be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ChiCTR2300076862.

Anesthesia-related intervention for long-term survival and cancer recurrence following breast cancer surgery: A systematic review of prospective studies.

OBJECTIVE: Anesthesia is correlated with the prognosis of cancer surgery. However, evidence from prospective studies focusing on breast cancer is currently limited. This systematic review aimed to investigate the effect of anesthesia-related interventions on oncological outcomes following breast cancer surgery in prospective studies. METHODS: Literature searches were performed from inception to June. 2023 in the Pubmed, Web of Science, Embase, and ClinicalTrials databases. The main inclusion criteria comprised a minimum of one-year follow-up duration, with oncological outcomes as endpoints. Anesthesia-related interventions encompassed, but were not limited to, type of anesthesia, anesthetics, and analgesics. The risk of bias was assessed using the Cochrane Risk of Bias Tool. RESULTS: A total of 9 studies were included. Anesthesia-related interventions included paravertebral nerve block (3), pectoral nerve block (1), sevoflurane (2), ketorolac (2), and infiltration of lidocaine (1). Cancer recurrence, metastasis, disease-free survival, or (and) overall survival were assessed. Among all included studies, only infiltration of lidocaine was found to prolong disease-free survival and overall survival. CONCLUSION: Regional anesthesia and propofol did not improve oncological outcomes following breast cancer surgery. The anti-tumorigenic effect of ketorolac warrants future studies with larger sample sizes. Perioperative infiltration of lidocaine around the tumor may be a promising anti-tumorigenic intervention that can prolong overall survival in patients with early breast cancer.

Associations of modern initial antiretroviral therapy regimens with all-cause mortality in people living with HIV in resource-limited settings: a retrospective multicenter cohort study in China.

Despite the proven virological advantages, there remains some controversy regarding whether first-line integrase strand transfer inhibitors (INSTIs)-based antiretroviral therapy (ART) contributes to reducing mortality of people living with HIV (PLHIV) in clinical practice. Here we report a retrospective study comparing all-cause mortality among PLHIV in China who were on different initial ART regimens (nevirapine, efavirenz, dolutegravir, lopinavir, and others [including darunavir, raltegravie, elvitegravir and rilpivirine]) between 2017 and 2019. A total of 41,018 individuals were included across China, representing 21.3% of newly reported HIV/AIDS cases collectively in the country during this period. Only the differences in all-cause mortality of PLHIV between the efavirenz group and the nevirapine group, the dolutegravir group and the nevirapine group, and the lopinavir group and the nevirapine group, were observed in China. After stratifying the cause of mortality, we found that the differences in mortality between initial ART regimens were mainly observed in AIDS-related mortality.

Immediate and long-term outcomes after treat-all among people living with HIV in China: an interrupted time series analysis.

BACKGROUND: In 2003, China implemented free antiretroviral therapy (ART) for people living with HIV (PLHIV), establishing an eligibility threshold of CD4 < 200 cells/µl. Subsequently, the entry criteria were revised in 2012 (eligibility threshold: CD4 ≤ 350 cells/µl), 2014 (CD4 ≤ 500 cells/µl), and 2016 (treat-all). However, the impact of treat-all policy on HIV care and treatment indicators in China is unknown. We aimed to elucidate the immediate and long-term impact of the implementation of treat-all policy in China. METHODS: Anonymized programmatic data on ART initiation and collection in PLHIV who newly started ART were retrieved between 1 January 2015 and 31 December 2019, from two provincial and municipal Centers for Disease Control and Prevention and ten major infectious disease hospitals specialized in HIV care in China. We used Poisson and quasi-Poisson segmented regression models to estimate the immediate and long-term impact of treat-all on three key indicators: monthly proportion of 30-day ART initiation, mean CD4 counts (cells/µl) at ART initiation, and mean estimated time from infection to diagnosis (year). We built separate models according to gender, age, route of transmission and region. RESULTS: Monthly data on ART initiation and collection were available for 75,516 individuals [gender: 83.8% males; age: median 39 years, interquartile range (IQR): 28-53; region: 18.5% Northern China, 10.9% Northeastern China, 17.5% Southern China, 49.2% Southwestern China]. In the first month of treat-all, compared with the contemporaneous counterfactual, there was a significant increase in proportion of 30-day ART initiation [+ 12.6%, incidence rate ratio (IRR) = 1.126, 95% CI: 1.033-1.229; P = 0.007] and mean estimated time from infection to diagnosis (+ 7.0%, IRR = 1.070, 95% CI: 1.021-1.120; P = 0.004), while there was no significant change in mean CD4 at ART initiation (IRR = 0.990, 95% CI: 0.956-1.026; P = 0.585). By December 2019, the three outcomes were not significantly different from expected levels. In the stratified analysis, compared with the contemporaneous counterfactual, mean CD4 at ART initiation showed significant increases in Northern China (+ 3.3%, IRR = 1.033, 95% CI: 1.001-1.065; P = 0.041) and Northeastern China (+ 8.0%, IRR = 1.080, 95% CI: 1.003-1.164; P = 0.042) in the first month of treat-all; mean estimated time from infection to diagnosis showed significant increases in male (+ 5.6%, IRR = 1.056, 95% CI: 1.010-1.104; P = 0.016), female (+ 14.8%, IRR = 1.148, 95% CI: 1.062-1.240; P < 0.001), aged 26-35 (+ 5.3%, IRR = 1.053, 95% CI: 1.001-1.109; P = 0.048) and > 50 (+ 7.8%, IRR = 1.078, 95% CI: 1.000-1.161; P = 0.046), heterosexual transmission (+ 12.4%, IRR = 1.124, 95% CI: 1.042-1.213; P = 0.002) and Southwestern China (+ 12.9%, IRR = 1.129, 95% CI: 1.055-1.208; P < 0.001) in the first month of treat-all. CONCLUSIONS: The implementation of treat-all policy in China was associated with a positive effect on HIV care and treatment outcomes. To advance the work of rapid ART, efforts should be made to streamline the testing and ART initiation process, provide comprehensive support services, and address the issue of uneven distribution of medical resources.

Influence of extent of surgical resection on post-hepatectomy shoulder pain: an observational study.

Shoulder pain frequently follows hepatectomy. However, the influence of surgical procedures on shoulder pain is unclear. In this observational study, patients who underwent hepatectomy were enrolled in Shanghai Cancer Center. Shoulder pain and surgical pain were assessed using the numeric rating scale 2 days after surgery. The incidence of shoulder pain was the outcome of the cohort study. Nested case-control analyses were further applied. Three hundred and twelve patients were finally enrolled in this study. Nested case-control analysis showed that there were no significant differences in the number of surgical segments between the two groups (P = 0.09). In addition, minor hepatectomy did not reduce the incidence of shoulder pain compared with major hepatectomy (P = 0.37). The drainage volume within 2 days after surgery was significantly more in those patients with shoulder pain (P = 0.017). In open surgery, surgical sites involving the right anterior lobe (OR (95% CI) 2.021 (1.075, 3.802), P = 0.029) and right posterior lobe (OR (95% CI) 2.322 (1.193, 4.522), P = 0.013) were both independent risk factors for shoulder pain. Left shoulder pain also occurred in patients who did not receive left lateral hepatectomy. The preventive phrenic nerve block was not suitable for post-hepatectomy shoulder pain. Stronger preventative intervention should be used in those high-risk patients.

Association of low-level viremia with mortality among people living with HIV on antiretroviral therapy in Dehong, Southwest China: A retrospective cohort study.

OBJECTIVES: To investigate the association of low-level viremia (LLV) with mortality among people living with HIV (PLHIV) on antiretroviral therapy (ART) in Dehong, Southwest China. METHODS: We analysed data collected from a cohort of PLHIV on ART in Dehong. PLHIV were enrolled in this cohort after they started ART, with viral load (VL) tested once a year afterwards. Each VL level was then categorized into one of the four groups: <50, 50-199, 200-999 and ≥1000 copies/ml. VL levels of 50-199 and 200-999 copies/ml were defined as LLV. The VL level for each participant was re-categorized and fitted into an extended Cox regression model as a time-varying covariate to examine the associations of VL level with all-cause and AIDS-related deaths. RESULTS: Among the included 7273 of 8762 PLHIV in this study, median age (interquartile range, IQR) was 36 (30-43) years and 59.9% were male. The patients were followed up for a median duration (IQR) of 6.2 (4.3-8.2) years. Compared with VL <50 copies/ml, LLV 200-999 copies/ml (adjusted hazard ratio [aHR] and 95% confidence interval [95% CI]: 1.56 [1.04, 2.32]) were associated with elevated risk of all-cause mortality and LLV50-199 (aHR [95% CI]: 1.00 [0.68, 1.45]) were not. Similarly, only LLV200-999 copies/ml (aHR [95% CI]: 2.37 [1.36, 4.14]) corresponded to higher risk of AIDS-related mortality. CONCLUSIONS: This study suggests that PLHIV on ART may have elevated death risks even though the viremia is suppressed at a low level. Interventions targeting PLHIV with LLV should be developed to reduce their mortality.

Incidence and risk factors for acute shoulder pain after hepatectomy: a nested case-control study.

BACKGROUND: Shoulder pain is commonly reported after hepatic surgery; however, the factors affecting post-hepatectomy shoulder pain remain unclear. This study aimed to determine the incidence and risk factors of shoulder pain after hepatectomy. METHODS: This prospective cohort study recruited 218 patients who underwent hepatic resection at our hospital from June to September 2022. Data were obtained from electronic medical records and follow-up assessments on the second postoperative day. All patients denied chronic pain before surgery. In this cohort study, patients were grouped according to the appearance of shoulder pain. Demographic information and perioperative data were compared between the two groups. The relationship between shoulder pain and independent variables was assessed using univariate binary logistic regression analysis. The potential risk factors were analyzed using multivariable binary logistic regression. RESULTS: Of the 218 patients enrolled in this cohort study, 91 (41.7%) reported shoulder pain. Patients in the case group were significantly younger than those in the control group (P = 0.001). Epidural anesthesia was used more frequently in the case group (P = 0.012). Patients over 60 years of age showed a lower incidence of shoulder pain than younger patients (P = 0.028). According to multivariable binary logistic regression analysis, advanced age and epidural anesthesia were associated with risk of shoulder pain (advanced age: odds ratio [OR] [95% confidence interval (CI)]: 0.96 [0.94, 0.99], P = 0.002; epidural anesthesia: OR [95% CI]: 2.08 [1.18, 3.69], P = 0.012). CONCLUSIONS: The incidence of acute shoulder pain after hepatectomy is 41.7%. The application of epidural anesthesia is an independent risk factor for shoulder pain after hepatectomy, whereas advanced age is a protective factor.

Longitudinal impact of compliance with routine CD4 monitoring on all cause deaths among treated people with HIV in China.

Keeping adherence to the continuous and standardized CD4 follow-up monitoring service is of great significance to the control of disease progression and the reduction of avoidable mortality for HIV-infected patients. As non-communicable diseases (NCDs) have become main causes of deaths for people with HIV (PWH) in the era of combination antiretroviral therapy (cART), how and to what extent does adherence to routine CD4 monitoring differentially impact on AIDS-related versus NCDs-related deaths in low- and middle-income countries (LMIC) remains elucidated. A CD4 test index was developed by dividing the actual number of received CD4 tests by the theoretical number of CD4 tests that should have been performed according to national treatment guidelines during the study period, with an index value of 0.8-1.2 reflecting compliance. From 1989 to 2020, 14,571 adults were diagnosed with HIV infection in Dehong Prefecture of Yunnan province in Southwestern China, 6,683 (45.9%) PWH had died with the all-cause mortality of 550.13 per 10,000 person-years, including 3,250 (48.6%) AIDS-related deaths (267.53 per 10,000 person-years). Among patients on cART, the median CD4 test index was 1.0 (IQR 0.6-1.3), and 35.2% had a CD4 test index less than 0.8. Cox proportional hazards regression analysis indicated that PWH with CD4 test index at 0.8-1.2 were at the lowest risk of both AIDS-related (aHR = 0.06; 95%CI: 0.05-0.07) and NCDs-related (aHR = 0.13; 95%CI: 0.11-0.16)deaths. Adherence to routine CD4 monitoring is critical for reducing both AIDS-related and NCDs-related mortality of PWH. An appropriate (once or twice a year) rather than an unnecessarily higher frequency of routine CD4 testing could be most cost-effective in reducing mortality in LMIC.

The impact of COVID-19 non-pharmaceutical interventions on HIV care continuum in China: An interrupted time series analysis.

Background: China implemented strict non-pharmaceutical interventions to contain COVID-19 at the early stage. We aimed to evaluate the impact of COVID-19 on HIV care continuum in China. Methods: Aggregated data on HIV care continuum between 1 January 2017 and 31 December 2020 were collected from centers for disease control and prevention at different levels and major infectious disease hospitals in various regions in China. We used interrupted time series analysis to characterize temporal trend in weekly numbers of HIV post-exposure prophylaxis (PEP) prescriptions, HIV tests, HIV diagnoses, median time intervals between HIV diagnosis and antiretroviral therapy (ART) initiation (time intervals, days), ART initiations, mean CD4+ T cell counts at ART initiation (CD4 counts, cells/µL), ART collections, and missed visits for ART collection, before and after the implementation of massive NPIs (23 January to 7 April 2020). We used Poisson segmented regression models to estimate the immediate and long-term impact of NPIs on these outcomes. Findings: A total of 16,780 PEP prescriptions, 1,101,686 HIV tests, 69,659 HIV diagnoses, 63,409 time intervals and ART initiations, 61,518 CD4 counts, 1,528,802 ART collections, and 6656 missed visits were recorded during the study period. The majority of outcomes occurred in males (55·3-87·4%), 21-50 year olds (51·7-90·5%), Southwestern China (38·2-82·0%) and heterosexual transmission (47·9-66·1%). NPIs was associated with 71·5% decrease in PEP prescriptions (IRR 0·285; 95% CI 0·192-0·423), 36·1% decrease in HIV tests (0·639, 0·497-0·822), 32·0% decrease in HIV diagnoses (0·680, 0·511-0·904), 59·3% increase in time intervals (1·593, 1·270-1·997) and 17·4% decrease in CD4 counts (0·826, 0·746-0·915) in the first week during NPIs. There was no marked change in the number of ART initiations, ART collections and missed visits during the NPIs. By the end of 2020, the number of HIV tests, HIV diagnoses, time intervals, ART initiations, and CD4 counts reached expected levels, but the number of PEP prescriptions (0·523, 0·394-0·696), ART collections (0·720, 0·595-0·872), and missed visits (0·137, 0·086-0·220) were still below expected levels. With the ease of restrictions, PEP prescriptions (slope change 1·024/week, 1·012-1·037), HIV tests (1·016/week, 1·008-1·026), and CD4 counts (1·005/week, 1·001-1·009) showed a significant increasing trend. Interpretation: HIV care continuum in China was affected by the COVID-19 NPIs at various levels. Preparedness and efforts to maintain the HIV care continuum during public health emergencies should leverage collaborations between stakeholders. Funding: Natural Science Foundation of China.

Untargeted Plasma Metabolomics Reveals Extensive Metabolic Alterations Among Treatment-Naive Human Immunodeficiency Virus/Hepatitis C Virus Co-Infected Patients with Liver Disease Progression.

Both human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may induce metabolic disorders and cause liver complications. Therefore, we aim to analyze the metabolite differences among treatment-naive HIV/HCV co-infected patients with versus without liver disease progression (LDP) and HIV mono-infected patients. A cross-sectional study was conducted in 65 HIV/HCV co-infected patients (22 with LDP and 43 without) and 65 HIV mono-infected patients in Dehong prefecture of Yunnan province, China. Plasma metabolomics were measured by gas chromatography-mass spectrometry (MS) and liquid chromatography-MS. Discrimination analysis, pathway enrichment analysis, generalized linear model with binomial distribution, and area under the receiver-operating characteristic curve (AUC) were conducted to identify bilateral differences in metabolites and pathways in different comparison groups. A total of 10,831 with 673 named and 10,158 unnamed metabolites were detected. Compared with HIV/HCV co-infected patients without LDP, phenylalanine, tyrosine, and tryptophan biosynthesis pathway with the increased level of tyrosine were significantly altered among HIV/HCV co-infected patients with LDP. Compared with HIV mono-infected patients, the decreased level of glutamine and increased levels of glutamic acid, arachidonic acid, and its derivatives were identified among HIV/HCV co-infected patients. Metabolite panels adjusted for baseline information had a higher accuracy than baseline model (without metabolite information) in distinguishing HIV/HCV co-infected patients with versus without LDP (AUC 0.951 vs. 0.849, p = .027) and HIV/HCV co-infected patients from HIV mono-infected patients (AUC 0.889 vs. 0.766, p < .001). A novel set of metabolites were found to discriminate HIV/HCV co-infected patients with versus without LDP, and from HIV mono-infected patients, which may have mechanistic and interventional implications.

Microbial translocation is associated with advanced liver fibrosis among people with HIV.

BACKGROUND: The prevalence of liver complications is increasing among people living with HIV, and microbial translocation (MT) might play a vital role. We conducted a prospective cohort study to evaluate the association between plasma biomarkers of MT and liver fibrosis (LF) among people living with HIV in southwest China. METHOD: A total of 665 people living with HIV were enrolled at baseline and had at least one follow-up visit during the 3-year study period. We calculated the Liver Fibrosis Index (FIB-4) to evaluate LF and measured plasma soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP) as surrogate biomarkers for MT. We used ordinal logistic regression to investigate correlates of LF at baseline and used a linear mixed model to examine the association between dynamic changes in MT biomarkers and LF. RESULTS: Of the participants, 61 (9.17%) had advanced LF (FIB-4 >3.25), and 193 (29.02%) had moderate LF (1.45 ≤ FIB-4 ≤ 3.25). Patients with advanced LF had higher plasma levels of sCD14 and LBP than those with moderate or no LF, both at baseline and at follow-up. The following factors were significantly associated with advanced LF: the highest quartile of LBP (adjusted odds ratio [aOR] = 1.69; 95% confidence interval [CI] 1.02~2.81), current intravenous drug use (aOR = 1.82; 95% CI 1.06~3.12), baseline CD4 <200 cells/µl (aOR = 3.25; 95% CI 2.13~4.95), hepatitis C virus coinfection (aOR = 2.52; 95% CI 1.41~4.51) and age >50 years (aOR = 32.66; 95% CI 15.89~66.36). LF progression (increasing FIB-4) was significantly associated with increasing sCD14 level (ß = 1.11; 95% CI 0.97~1.26; p < 0.001) with covariate adjustment. CONCLUSION: The significant relationship between MT and LF may reveal pathogenic mechanisms and potential intervention targets of liver complications among people living with HIV in China.

Increase in HIV-1-transmitted drug resistance among ART-naïve youths at the China-Myanmar border during 2009 ~ 2017.

BACKGROUND: HIV-transmitted drug resistance (TDR) is found in antiretroviral therapy (ART)-naïve populations infected with HIV-1 with TDR mutations and is important for guiding future first- and second-line ART regimens. We investigated TDR and its effect on CD4 count in ART-naïve youths from the China-Myanmar border near the Golden Triangle to better understand TDR and effectively guide ART. METHODS: From 2009 to 2017, 10,832 HIV-1 infected individuals were newly reported along the Dehong border of China, 573 ART-naïve youths (16 ~ 25 y) were enrolled. CD4 counts were obtained from whole blood samples. HIV pol gene sequences were amplified from RNA extracted from plasma. The Stanford REGA program and jpHMM recombination prediction tool were used to determine genotypes. TDR mutations (TDRMs) were analyzed using the Stanford Calibrated Population Resistance tool. RESULTS: The most common infection route was heterosexuals (70.51%), followed by people who inject drugs (PWID, 19.20%) and men who have sex with men (MSM) (8.90%). The distribution of HIV genotypes mainly included the unique recombinant form (URF) (44.08%), 38.68% were CRFs, 13.24% were subtype C and 4.04% were subtype B. The prevalence of TDR increased significantly from 2009 to 2017 (3.48 to 9.48%) in ART-naïve youths (4.00 to 13.16% in Burmese subjects, 3.33 to 5.93% in Chinese subjects), and the resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) were 3.49, 2.62, and 0.52%, respectively. Most (94.40%, n = 34) of HIV-1-infected patients with TDRM had mutation that conferred resistance to a single drug class. The most common mutations Y181I/C and K103N, were found in 7 and 9 youths, respectively. The mean CD4 count was significantly lower among individuals with TDRMs (373/mm3 vs. 496/mm3, p = 0.013). CONCLUSIONS: The increase in the prevalence of HIV-1 TDR increase and a low CD4 count of patients with TDRMs in the China-Myanmar border suggests the need for considering drug resistance before initiating ART in HIV recombination hotspots.

Plasma Inflammatory Biomarkers Associated with Advanced Liver Fibrosis in HIV-HCV-Coinfected Individuals.

BACKGROUND: HIV and HCV coinfection leads to accelerated liver fibrosis, in which microbial translocation and systemic inflammation might play important roles. OBJECTIVE: This study aimed to provide an extensive profile of the plasma microbial translocation and inflammation biomarkers associated with advanced liver fibrosis among HIV-HCV-coinfected patients. METHODS: This cross-sectional study recruited 343 HIV-HCV-coinfected patients on combination antiretroviral therapy (cART) from a rural prefecture of Yunnan province in Southwest China. The plasma concentrations of sCD14 and 27 cytokines and chemokines were assayed and compared against advanced or mild levels of liver fibrosis. RESULTS: Of the 343 HIV-HCV-coinfected patients, 188 (54.8%) had severe or advanced liver fibrosis (FIB-4 > 3.25). The patients with advanced liver fibrosis (FIB-4 > 3.25 vs. FIB-4 ≤ 3.25) had higher plasma levels of interleukin (IL)-1ß, IL-6, IL-7, IL-9, IL-12, IL-15, IL-17, granulocyte macrophage colony stimulating factor (GM-CSF), Interferon-γ (IFN-γ), tumor necrosis factor (TNF-α), IL-4, IL-10, IL-13, fibroblast growth factor 2 (FGF-basic), and Monocyte chemoattractant protein-1 (MCP-1). Multivariable logistic regression models showed that advanced liver fibrosis was associated with an increased plasma level of IL-1ß, IL-6, IL-7, IL-12, IL-17, GM-CSF, IFN-γ, IL-4, IL-10, MCP-1, Eotaxin, and FGF-basic, with FGF-basic continuing to be positively and significantly associated with advanced liver fibrosis, after Bonferroni correction for multiple comparisons (adjusted odds ratio (aOR) = 1.92; 95%CI: 1.32-2.81; p = 0.001). Plasma sCD14 was also significantly associated with advanced liver fibrosis (aOR = 1.13; 95%CI: 1.01-1.30; p = 0.049). CONCLUSIONS: HIV-HCV-coinfected patients are living with a high prevalence of advanced liver fibrosis which coexists with a mixture of elevated plasma inflammation and microbial translocation biomarkers. The significant associations of advanced liver fibrosis with FGF-basic and sCD14 may reveal pathogenic mechanisms and potential clinical intervention targets for liver fibrosis in HCV-HIV coinfection.

Fibrosis-4 index predicts mortality in HIV/HCV co-infected patients receiving combination antiretroviral therapy in rural China.

End-stage liver disease (ESLD) is among leading causes of death for people living with HIV and HCV. Little is known how liver fibrosis score predicts mortality in HIV/HCV co-infected population under combination antiretroviral therapy (cART). A retrospective cohort study of 691 HIV/HCV co-infected patients receiving cART in Yunnan, China from 2005 to 2016 was carried out to explore the association between Fibrosis-4 index (FIB-4) and all-cause mortality. Cox proportional hazard models were used to estimate the hazard ratios (HRs) for FIB-4 and covariates. After a median follow-up of 4.8 years with a total follow-up time of 3,696 person-years (PY), 131 deaths occurred and the all-cause mortality was 3.5 per 100 PY. The mortality was 2.9 (95% CI: 2.3-3.5)/100 PY for the FIB-4 ≤ 3.25 group and 5.8 (4.2-7.4)/100 PY for the FIB-4 > 3.25 group at baseline. People with FIB-4 changed from mild to advanced group showed HR of 1.81 (95% CI: 1.01-3.25) for death, and with FIB-4 sustaining advanced showed HR of 3.11 (1.75-5.54), both compared to those with FIB-4 remained mild, while lower risk of death was observed among married people (HR = 0.63, 95% CI: 0.41-0.99) compared to unmarried, among those with most recent CD4+ T cell counts between 200 and 350 cells/µL (0.50, 0.30-0.86) and > 350 cells/µL (0.25, 0.15-0.41) compared to CD4 under 200 cells/µL. Advanced and progressive liver fibrosis is a strong predictor of all-cause mortality in HIV/HCV co-infected patients under cART in China.

Synergistic anticancer effect of Grb2 and ITGA1 on cancer cells highly expressing Grb2 through suppressing ERK phosphorylation.

BACKGROUND: Growth factor receptor bound protein 2 (Grb2) is known to be an adaptor protein that provides a critical link between cell surface growth factor receptors and the MAPK signaling. It was shown that high expression of Grb2 enhances cancer cells proliferation, invasion and malignant transformation. OBJECTIVE: In this study, we aimed to systemically understand the function of Grb2 in cancer. METHODS: The expression of Grb2 in different cancer cell lines was examined from a publicly available database and we chose two cancer cell lines highly expressing Grb2 to investigate the role of Grb2. To systemically understand the function of Grb2 in cancer cells, proteomic profiles also were analyzed. RESULT: The results suggested that downregulation of Grb2 reduced cell proliferation in Hela cells and Jurkat cells. In addition, knockdown of Grb2 reduced the expression of ITGA1 and inhibited the phosphorylation of ERK. Intriguingly, simultaneous inhibition of Grb2 and ITGA1 resulted in a greater inhibition of phosphorylated ERK than either inhibition of Grb2 or ITGA1, and thus triggered marked apoptosis in Hela cells and Jurkat cells. These results suggest a synergistic anticancer effect of Grb2 and ITGA1 mediated by the ERK pathway in cancer cells highly expressing Grb2. In conclusion, we provided evidence that inhibition of Grb2 and ITGA1 might be an attractive target for therapeutic intervention against the cancer growth of cancers with high Grb2 expression.

Effect of community-based extension clinics of methadone maintenance therapy for opiate-dependent clients: A prospective cohort study in Dehong Prefecture, Yunnan Province of China.

Methadone maintenance therapy (MMT) is effective in treatment of opiate dependents. However, there is a gap between the coverage of standard MMT clinics and the need of opiate dependents. Establishment of extension clinics of methadone maintenance therapy (EMMT) will increase the coverage and improve MMT accessibility. We implemented a prospective cohort study to understand the effects of establishment of community-based EMMT clinics comparing with MMT clinics in Yunnan Province.A total of 462 opiate-dependent clients were interviewed from the community-based EMMT clinics and standard MMT clinics located in 5 counties of Mangshi, Ruili, Longchuan, Yingjiang, and Lianghe in Yunnan Province. The information on the demographic characteristics, drug risk behaviors, quality of life (QOL), and urine testing results for morphine of the clients was collected and compared between the EMMT and MMT clinics. A survival analysis method was utilized to know the retention situation of the newly enrolled clients with Kaplan-Meier method during 9 months treatment.Among the EMMT clients, 96.9% were male; 31.4% were Han; 61.4% were married; 39.0% had primary school education; 95.5% lived with their family or relatives; 96.9% who arrived the clinic less than 15 min; 52.9% had used drugs for more than 10 years; and 16.7% injected drug. After 9 months therapy, there was no difference in the changes of life quality such as physical and psychological features, social relationships, environmental function, and total QOL and well-being between those of EMMT and MMT clinics. The positive detection rate of urine-morphine testing among newly enrolled clients of EMMT clinics decreased as the period of treatment lengthened. The average time of retention for newly enrolled EMMT clients who are still receiving the treatment was 175 days. And the average time from initiations to drop-out of treatment for newly enrolled EMMT clients was 122 days. The 9-month retention rates of the clients were 52.1% and 60.9% at EMMT and MMT clinics, respectively.The effect on EMMT retention was the same as that of MMT. Establishment of EMMT clinics was an effective strategy to expand the coverage of MMT and increase the retention of opiate dependents in the rural areas of the counties.

Let­7i­5p inhibits the proliferation and metastasis of colon cancer cells by targeting kallikrein­related peptidase 6.

Colorectal cancer is one of the most common types of malignancies worldwide, and as it is often diagnosed at an advanced stage, it is a serious threat to human health. MicroRNAs are important regulators of the growth and metastasis of colon cancer (CC). In the present study, the results demonstrated that kallikrein­related peptidase 6 (KLK6) plays a critical role in suppressing colon carcinoma progression. To further investigate whether microRNAs affect the impact of KLK6, a bioinformatics approach was employed, which indicated that let­7i­5p may directly target KLK6. Furthermore, the expression level of let­7i­5p was significantly negatively correlated with the expression of KLK6 at the mRNA and protein levels in CC. Functionally, overexpression of let­7i­5p inhibited the proliferation and invasion of CC cells, and suppressed the growth of CC in vitro. The luciferase reporter assays revealed that let­7i­5p targeted the KLK6 3'­untranslated region. Collectively, these results indicated that let­7i­5p inhibited the proliferation and metastasis of CC cells by targeting KLK6, thereby blocking the cell cycle and promoting apoptosis in colon cells. Therefore, the present study revealed that the let­7i­5p/KLK6 axis may be a potential target for new therapeutic strategies to treat colon tumors.

FL118, a novel camptothecin analogue, suppressed migration and invasion of human breast cancer cells by inhibiting epithelial-mesenchymal transition via the Wnt/ß-catenin signaling pathway.

The aim of the current study was to investigate the effects of FL118, a novel camptothecin analogue, on migration and invasion of human breast cancer cells and the underlying mechanisms of those effects. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and a plate clone formation assay were used to examine inhibition of the proliferation of MDA-MB-231 cells by FL118. Cell cycle distribution was detected using flow cytometry. A wound healing assay and a transwell assay were performed to detect the effects of FL118 on migration and invasion of MDA-MB-231 cells, respectively. qRT-PCR, Western blotting, and immunocytochemistry were used to study the effects of FL118 on expression of epithelial-mesenchymal transition (EMT)-related molecules and Wnt/ ß-catenin signaling components in MDA-MB-231 cells. The current results indicated that FL118 inhibited the proliferation, migration and invasion of MDA-MB-231 cells in a dose- and time-dependent manner. FL118 caused MDA-MB-231 cells to accumulate in the S phase. FL118 significantly suppressed the expression of vimentin while enhancing the expression of E-cadherin. Moreover, decreased expression of ß-catenin and its targets survivin and cyclin Dl was detected in the nucleus of MDA-MB-231 cells. Taken together, the current results suggest that FL118 inhibited Wnt/ß-catenin signaling, leading to suppressed EMT and decreased migration and invasion of breast cancer cells.

Tobacco and alcohol use among drug users receiving methadone maintenance treatment: a cross-sectional study in a rural prefecture of Yunnan Province, Southwest China.

OBJECTIVE: To estimate the prevalence of ever, current and heavy tobacco and alcohol use and their correlates among patients undergoing methadone maintenance treatment (MMT). DESIGN: Cross-sectional study. SETTING: The study was conducted in all of the 5 MMT clinics in Dehong Prefecture, China. PARTICIPANTS: 2121 (81.6%) eligible MMT participants were included in the study population. ANALYSIS: Ordinal logistic regression was used to estimate the ORs and their 95% CIs. RESULTS: The overall prevalence of ever, current and heavy smoking was 98.6%, 97.8% and 66.3%, respectively; while that of ever, current and hazardous alcohol drinking was 86.6%, 58.6% and 16.6%, respectively. Among HIV-infected participants, the proportions of those experiencing harmful effects of tobacco and alcohol on AIDS were 53.6% and 72.5%, respectively, and 16.9% and 49.3% had ever tried to quit after diagnosis with HIV. After adjusting for potential confounders, heavier smokers and more hazardous drinkers were more likely to be men, older and less educated. Ethnic minorities were less likely to heavily smoke, but more likely to engage in hazardous drinking. In addition, hazardous drinking was negatively associated with longer years of MMT and HIV infection. Moreover, heavier smoking (OR≥2=2.08, 95% CI 1.16 to 3.73) and more hazardous drinking (OR≥2=2.46, 95% CI 1.53 to 3.97) were positively associated with having multiple sexual partners, and both were positively associated with each other. CONCLUSIONS: The prevalence of tobacco and alcohol consumption was extraordinarily high among MMT participants in China, suggesting the urgent need of enhancing MMT patients' awareness of the harmful effects of tobacco and alcohol consumption and implementing comprehensive education and effective intervention programmes.

[Incidence and risk factors of HIV infection among sero-negative spouses of people living with HIV/AIDS in Dehong prefecture, Yunnan province].

OBJECTIVE: To study the incidence rate and risk factors of HIV infection among sero-negative spouses of people living with HIV/AIDS (HIV/AIDS) in Dehong prefecture, Yunnan province. METHODS: A prospective cohort study was conducted from February 2009 to December 2014 in Dehong prefecture, Yunnan province. Questionnaire survey and HIV related tests were carried out once a year. RESULTS: By the end of December 2014, 2 091 sero-negative spouses had been recruited, of whom 1 692 were followed-up for at least one time. RESULTS showed that 34 new HIV infections were identified within 5 494.52 person years of follow-up, for an overall incidence of 0.62 per 100 person years. HIV incidence rates appeared as 0.79 per 100 person years, 0.62 per 100 person years, 0.47 per 100 person years in 2009-2010, 2011-2012, 2013-2014, respectively. Data from the Cox proportional hazard regression model indicated that risk factors of HIV infection among sero-negative spouses of HIV/AIDS were: non-consistent condom use (HR=4.64, 95%CI: 1.89-11.40,P= 0.001), HIV/AIDS delayed antiviral retrovirus therapy (ART) for more than one year (HR=3.70, 95% CI: 1.44-9.49,P=0.007) after the HIV negative spouses were initially recruited, HIV/AIDS did not receive any ART (HR=3.62, 95% CI: 1.14-11.51,P=0.029). CONCLUSIONS: The incidence of HIV infection among sero-negative spouses in Dehong prefecture was relatively low. Publicity on consistent condom use program should be emphasized among sero-negative spouses of HIV/AIDS, together with the timely provision of ART to those HIV/AIDS.