Intermittent fasting attenuates lipopolysaccharide-induced acute lung injury in mice by modulating macrophage polarization.

Acute lung injury (ALI) is a spectrum of acute and life-threatening pulmonary inflammatory conditions. Treatment of ALI remains a clinical challenge. Recently, intermittent fasting (IF) has been shown to improve health and alleviate many diseases. In this study, we tested whether IF attenuated ALI and investigated the mechanism underlying this process. In vivo, the effects of IF on ALI were evaluated in a lipopolysaccharide (LPS)-induced murine ALI model. We found that two times of 24-h fasting in a week before ALI efficiently ameliorated LPS-induced lung injury in mice, characterized by alleviated lung lesions, wet-to-dry weight ratio, myeloperoxidase activity, malondialdehyde content, and lower levels of tumor necrosis factor-α, interleukin-6, and interleukin-1ß. In vitro, functional assays were conducted to assess IF on the inflammatory response and macrophage polarization of bone marrow-derived macrophages (BMDMs) treated with LPS or IL-4. And PPARγ antagonist GW9662 and AMPK siRNA were used to test the role of PPARγ and AMPK in the IF-mediated improvement of ALI. The results showed that IF (serum deprivation) suppressed macrophage M1 activation and promoted M2 activation in LPS-treated BMDMs. While, IF also augmented macrophage M2 polarization in IL-4-treated BMDMs. Further mechanistic studies showed that the promotive effect of IF on M2 polarization was related to the activation of the PPARγ and AMPK pathways. In conclusion, this study suggests that IF enhances M2 polarization by activating the AMPK and PPARγ pathways, thus facilitating anti-inflammatory response and ameliorating ALI.

Efficacy and Safety of Voriconazole Versus Amphotericin B Deoxycholate Induction Treatment for HIV-Associated Talaromycosis: A Prospective Multicenter Cohort Study in China.

INTRODUCTION: Current guidelines recommend amphotericin B as the preferred drug for induction therapy; however, amphotericin B is not available in certain settings. Induction therapy with amphotericin B deoxycholate or voriconazole has been shown to be an effective treatment for talaromycosis. However, prospective clinical trials comparing these two antifungal drugs are absent from the literature. METHODS: In this open-labeled, multicenter, prospective controlled trial, we enrolled patients at 15 hospitals in China from 2019 to 2020. Participants received induction treatment with either amphotericin B deoxycholate intravenously at a dose of 0.5 to 0.7 mg per kilogram per day or voriconazole at a dose of 6 mg/kg intravenously twice daily for the first day, followed by 4 mg/kg intravenously twice daily for 3 days, and then voriconazole was given either intravenously (4 mg/kg intravenously twice daily) or orally (200 mg twice daily) for the remaining 10 days. The primary outcome was all-cause mortality during 48 weeks after baseline. Secondary outcomes were mortality at week 2 or week 24, clinical resolution of talaromycosis, and fungal clearance at week 2. A propensity score (PS) matching analysis was performed to control confounding factors. RESULTS: We observed no difference in the risk of death at week 2, at week 24, or at week 48 in either the unmatched cohort or the matched cohort. Both in the unmatched and the matched cohorts, logistic regression analysis revealed a significantly lower odds ratio of clinical resolution (OR 0.450, 95% CI 0.291-0.696, p < 0.001; OR 0.443, 95% CI 0.261-0.752, p = 0.003) and fungal clearance (OR 0.514, 95% CI 0.333-0.793, p = 0.003; OR 0.542, 95% CI 0.318-0.923, p = 0.024) in voriconazole users compared to amphotericin B deoxycholate users over the course of 2 weeks. In the induction therapy without ART subgroup patients in the amphotericin B deoxycholate group showed a significantly higher rate of clinical resolution and fungal clearance than those in the voriconazole group (56.1% vs. 30.4%, 95% CI 13.4-36.5, p = 0.000; 63.8% vs. 40.4%, 95% CI 11.1-34.7, p = 0.000), whereas there was no significant difference in clinical resolution and fungal clearance in the induction therapy combined with ART subgroup. CONCLUSIONS: Induction therapy using voriconazole had a similar efficacy, in terms of all-cause mortality rate, to induction therapy using amphotericin B deoxycholate in HIV-infected patients with talaromycosis over a 48-week observation period. Amphotericin B deoxycholate contributed to earlier fungal clearance and earlier clinical resolution of symptoms in the induction therapy without ART subgroup, whereas amphotericin B deoxycholate use did not contribute to a significant difference in clinical resolution and fungal clearance in the induction therapy combination with ART subgroup. TRIAL REGISTRATION: ChiCTR1900021195. Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

Talaromyces marneffei activates the AIM2-caspase-1/-4-GSDMD axis to induce pyroptosis in hepatocytes.

Talaromyces marneffei tends to induce systemic infection in immunocompromised individuals, which is one of the causes of the high mortality. The underlying molecular mechanisms of T.marneffei-induced abnormal liver function are still poorly understood. In this study, we found that T.marneffei-infected patients could develop abnormal liver function, evidenced by reduced albumin and increased levels of aspartate aminotransferase (AST) and AST/alanine aminotransferase (ALT). T. marneffei-infected mice exhibited similar characteristics. In vitro investigations showed that T.marneffei induced the death of AML-12 cells. Furthermore, we determined that T.marneffei infection induced pyroptosis in hepatocytes of C57BL/6J mice and AML-12 cells, demonstrated by the increase of AIM2, caspase-1/-4, Gasdermin D(GSDMD) and pyroptosis-related cytokines in T.marneffei-infected mice/cells. Importantly, cell death was markedly suppressed in the presence of VX765 (an inhibitor of caspase-1/-4). Furthermore, in the presence of VX765, T.marneffei-induced pyroptosis was blocked. Nevertheless, necroptosis and apoptosis were also detected in infected animal model at 14 days post-infection. In conclusion, T.marneffei induces pyroptosis in hepatocytes through activation of the AIM2-caspase-1/-4-GSDMD axis, which may be an important cause of liver damage, and other death pathways including necroptosis and apoptosis may also be involved in the later stage of infection.

No Statistically Apparent Difference in Antifungal Effectiveness Observed Among Trimethoprim/Sulfamethoxazole Plus Clindamycin or Caspofungin, and Trimethoprim/Sulfamethoxazole Monotherapy in HIV-Infected Patients with Moderate to Severe Pneumocystis Pneumonia: Results of an Observational Multicenter Cohort Study.

INTRODUCTION: Pneumocystis pneumonia is a common opportunistic infection in patients with HIV/AIDS, and is a leading cause of death in this population. Early selection of effective treatment is therefore critical to reduce mortality. We conducted a clinical trial to compare the effectiveness and safety of three different antifungal treatment regimens in HIV-infected patients with moderate to severe PCP. METHODS: Our study was a multicenter, observational prospective clinical trial. We recruited 320 HIV-infected patients with moderate to severe PCP, and stratified these subjects into a trimethoprim/sulfamethoxazole (TMP-SMX) monotherapy group, a TMP-SMX plus clindamycin group, and a TMP-SMX plus caspofungin group. Patients were invited to participate in 12 weeks of follow-up. Outcomes included the difference in overall mortality and the proportion of overall positive response to treatment in the three groups at weeks 4 and 12, the difference in treatment duration, and the proportion of adverse events among the three groups during the study period. RESULTS: The probability of survival not statistically different among three treatment groups. Mortality in the TMP-SMX monotherapy group (group 1) was 15/115 (13.04%) vs. 20/83 (24.10%) in the TMP-SMX plus clindamycin group (group 2) vs. 24/107 (22.43%) in the TMP-SMX plus caspofungin group (group 3) at week 12 (p = 0.092). The overall positive response rate to treatment in the three groups was 24.14%, 34.94%, and 38.32%, respectively, at week 4, and 33.91%, 38.55%, and 44.86%, respectively, at week 12. No significant difference in the overall positive response rate to treatment at either week 4 or week 12 was noted (p = 0.061, p = 0.246). Rates of changes to therapy were 6.50% (8/123) in group 1, 3.40% (3/87) in group 2, and 2.70% (3/110) in group 3, and did not differ significantly among the three groups (p = 0.376). There were also no significant differences in adverse events among the three treatment groups of patients with moderate to severe PCP. CONCLUSIONS: Our results indicate that there are no significant statistical differences among the three studied treatment regimens in terms of antifungal effectiveness in HIV-infected patients with moderate to severe PCP. TMP-SMX monotherapy is a convenient, cheap, and effective therapeutic drug regimen to treat HIV-infected patients with moderate to severe PCP, and is an appropriate treatment strategy in resource-limited settings. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov , ID: ChiCTR1900021195. Registered on February 1, 2019.

Predictive factors of ART adherence in people living with HIV in Guangxi, China: a retrospective cross-sectional study.

Adherence to antiretroviral therapy (ART) is a prerequisite to improve immunity and reduce the morbidity and mortality of people living with HIV (PLWH). To describe ART adherence and associated factors among PLWH, patients who initiated ART in Liuzhou between 1998 and 2013 were recruited. Socio-demographic characteristics, HIV infection-related characteristics and clinical tests were analyzed. Both descriptive and multi-level analyses were used to explore factors related to ART adherence of PLWH who initiated ART in Liuzhou. A total of 8433 patients were recruited in this study. The rate of adherence to ART was 84.9% in PLWH who initiated ART in Liuzhou between 1998 and 2013. The female sex, WHO clinical stage III or IV before ART initiation, longer treatment duration and higher triglyceride were positively associated with ART adherence. Meanwhile, HIV acquired by intravenous drug use, co-infection with tuberculosis and other opportunistic infections were negatively associated with ART adherence. Measures should be adopted to improve the ART adherence of PLWH who are male, acquired HIV by intravenous drug use, and are co-infected with tuberculosis and other opportunistic infections.

HIV-associated talaromycosis: Does timing of antiretroviral therapy matter?

OBJECTIVES: No current academic data is available with respect to the optimal timing to initiate antiretroviral therapy (ART) in HIV-positive patients with talaromycosis. Our study aimed to evaluate the optimal timing of ART initiation for patients presenting with AIDS-related talaromycosis. METHODS: In this prospective, randomized, open-label multicenter trial, 228 patients from 15 hospitals in China were randomly assigned to an early ART group (initiation of ART within 2 weeks after randomization) and a deferred ART group (initiation of ART 2 weeks after randomization). The primary endpoint was all-cause mortality during the 48 weeks after randomization. RESULTS: We observed a significant difference in mortality between the early ART group and the deferred ART group (2.2% vs. 8.9%, 95%CI: -0.15 to 14.05, p = 0.049). The composite outcome of AIDS-defining events or death in the early ART group was found to be lower than that in the deferred ART group (3.3% vs. 14.9%; 95%CI: 2.93 to 19.23, p = 0.008). CONCLUSIONS: The prognosis of HIV-infected patients with talaromycosis in the early ART group was more favorable than that of patients in the deferred ART group. These results demonstrate that early ART initiation should be considered in HIV-infected patients with talaromycosis .

Establishment of a novel scoring model for mortality risk prediction in HIV-infected patients with cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) remains a leading cause of death in HIV-infected patients, despite advances in CM diagnostic and therapeutic strategies. This study was performed with the aim to develop and validate a novel scoring model to predict mortality risk in HIV-infected patients with CM (HIV/CM). METHODS: Data on HIV/CM inpatients were obtained from a Multicenter Cohort study in China. Independent risk factors associated with mortality were identified based on data from 2013 to 2017, and a novel scoring model for mortality risk prediction was established. The bootstrapping statistical method was used for internal validation. External validation was performed using data from 2018 to 2020. RESULTS: We found that six predictors, including age, stiff neck, impaired consciousness, intracranial pressure, CD4+ T-cell count, and urea levels, were associated with poor prognosis in HIV/CM patients. The novel scoring model could effectively identify HIV/CM patients at high risk of death on admission (area under curve 0.876; p<0.001). When the cut-off value of 5.5 points or more was applied, the sensitivity and specificity was 74.1 and 83.8%, respectively. Our scoring model showed a good discriminatory ability, with an area under the curve of 0.879 for internal validation via bootstrapping, and an area under the curve of 0.886 for external validation. CONCLUSIONS: Our developed scoring model of six variables is simple, convenient, and accurate for screening high-risk patients with HIV/CM, which may be a useful tool for physicians to assess prognosis in HIV/CM inpatients.

Multicentre derivation and validation of a prognostic scoring system for mortality assessment in HIV-infected patients with talaromycosis.

BACKGROUND: Although the widespread use of modern antiretroviral therapy (ART) has reduced the incidence of talaromycosis in people living with HIV, mortality remains as high as 20% in this population, even after appropriate antifungal treatment. OBJECTIVES: The objective of our study was to develop a risk assessment system for HIV-infected patients with comorbid talaromycosis, in order to provide these patients with appropriate, effective and potentially life-saving interventions at an early stage of their illness. PATIENTS/METHODS: This was a multicentre, retrospective cohort study conducted in China. We built a predictive model based on data from 11 hospitals, and a validated model using the data of 1 hospital located in an endemic area. RESULTS: Forward stepwise multivariate statistical calculations indicated that age, aspartate aminotransferase/alanine transaminase ratio and albumin levels, and BUN levels were valid, independent predictors of the risk of death in HIV-infected patients with talaromycosis. Our developed and validated risk scoring system is effective for the identification of HIV-infected patients with talaromycosis at high risk of death at hospital admission (p < .001; AUC = 0.860). In our study, our risk prediction model provided functional and robust discrimination in the validation cohort (p < .001; AUC = 0.793). CONCLUSION: The prognostic scoring system for mortality assessment developed in the present study is an easy-to-use clinical tool designed to accurately assist clinicians in identifying high-risk patients with talaromycosis.

Development of a risk scoring system for prognostication in HIV-related toxoplasma encephalitis.

BACKGROUND: This study aims to evaluate specific risk factors influencing prognosis of HIV-infected patients with toxoplasma encephalitis (TE) in order to develop a prognostic risk scoring system for them. METHODS: This is a six-center retrospective study of hospitalized HIV/TE patients. Data including six-week mortality after diagnosis, baseline characteristics, clinical features, laboratory tests and radiological characteristics of eligible patients were assimilated for risk model establishing. RESULTS: In this study, the six-week mortality among 94 retrospective cases was 11.7% (11/94). Seven specific risk factors, viz. time from symptom onset to presentation, fever, dizziness, CD4+ T-cell counts, memory deficits, patchy brain lesions, and disorders of consciousness were calculated to be statistically associated with mortality. A criterion value of '9' was selected as the optimal cut-off value of the established model. The AUC of the ROC curve of this scoring model was 0.976 (p < 0.001). The sensitivity and specificity of the risk scoring model was 100.0 and 86.9%, respectively, which were 81.8 and 94.1% of this scoring model in the verification cohort, respectively. CONCLUSIONS: The developed scoring system was established with simple risk factors, which also allows expeditious implementation of accurate prognostication, and appropriate therapeutic interventions in HIV-infected patients with TE.

Achieving High Thermoelectric Performance in p-Type BST/PbSe Nanocomposites through the Scattering Engineering Strategy.

To achieve high thermoelectric conversion efficiency in Bi0.4Sb1.6Te3 (BST) alloy is vital for its applications in low-grade energy harvesting. Here, we show that 56% increase in the power factor (PF) (from 16 to 25 µW cm-1 K-2) and 32% reduction of lattice thermal conductivity κL (from 0.56 to 0.38 W m-1 K-1) as well as an approximately four-fold decrease in bipolar-effect contribution κb (from 0.48 to 0.12 W m-1 K-1) can be achieved at 512 K through the incorporation of 0.2 vol % PbSe nanoparticles in the BST matrix. Analyses indicate that the remarkable increase in PF for the composite samples can be mainly attributed to strong electron scattering at the large interface barriers, inhibiting effectively the electron contribution to the total thermopower at elevated temperatures, while the large drop of κL and κb originates from enhanced phonon scattering by PbSe nanoinclusions as well as phase boundaries (among BST and PbSe nanophase) and suppression of electron transport, respectively. As a result, a maximum figure of merit (ZT) of 1.56 (at 400 K) and an average ZT (ZTave) of 1.44 in the temperature range of 300-512 K are reached. Correspondingly, a record projected conversion efficiency η = 11% is achieved at the cold side 300 K and hot side 512 K in the BST-based composite incorporated with 0.2 vol % PbSe nanoinclusions.

Improving the efficacy of conventional therapy by adding andrographolide sulfonate in the treatment of severe hand, foot, and mouth disease: a randomized controlled trial.

Background. Herb-derived compound andrographolide sulfonate (called Xiyanping injection) recommended control measure for severe hand, foot, and mouth disease (HFMD) by the Ministry of Health (China) during the 2010 epidemic. However, there is a lack of good quality evidence directly comparing the efficacy of Andrographolide Sulfonate combination therapy with conventional therapy. Methods. 230 patients were randomly assigned to 7-10 days of Andrographolide Sulfonate 5-10 mg/Kg/day and conventional therapy, or conventional therapy alone. Results. The major complications occurred less often after Andrographolide Sulfonate (2.6% versus 12.1%; risk difference [RD], 0.94; 95% CI, 0.28-1.61; P = 0.006). Median fever clearance times were 96 hours (CI, 80 to 126) for conventional therapy recipients and 48 hours (CI, 36 to 54) for Andrographolide Sulfonate combination-treated patients (χ(2) = 16.57, P < 0.001). The two groups did not differ in terms of HFMD-cause mortality (P = 1.00) and duration of hospitalization (P = 0.70). There was one death in conventional therapy group. No important adverse event was found in Andrographolide Sulfonate combination therapy group. Conclusions. The addition of Andrographolide Sulfonate to conventional therapy reduced the occurrence of major complications, fever clearance time, and the healing time of typical skin or oral mucosa lesions in children with severe HFMD.

[A comparison between clinical value of the liver transplantation standard mathematical model score and Child-Turcotte-Pugh score in evaluating the prognosis of liver failure].

OBJECTIVE: To compare the clinical value of the liver transplantation standard (LTS) mathematical model score and Child-Turcotte-Pugh (CTP) score in evaluating the prognosis of liver failure. METHODS: The clinical data of 150 liver failure patients were analyzed retrospectively. All the patients who were admitted from January 2004 to December 2008 were divided into survival group (n=48) and death group (n=102) in regard to their 90-day survival after their admission. LTS score and CTP score were calculated according to their respective clinical data within 24 hours after their admission. Comparison between LTS score and CTP score was conducted respectively between the survival group and death group. The correlation between LTS score/CTP score and the prognosis of liver failure was made by Spearman rank correlation. The ability of LTS score and CTP score to predict the outcome of liver failure was compared with the receiver operating characteristic (ROC) curve. RESULTS: The LTS score and CTP score of survival group were 38.88+/-4.27 and 11.25+/-0.97, respectively, which were lower than those of death group (52.63+/-10.65 and 12.18+/-1.22, both P<0.01). The correlation coefficient of LTS score and the prognosis of liver failure (r(s)=0.651, P<0.01) was higher than that of CTP score (r(s)=0.366, P<0.01). The area under ROC curve (AUC) of LTS score was 0.897, sensitivity (SN) was 76.52%, specificity (SP) was 91.18%, positive predictive value (PV+) was 94.39%, negative predictive value (PV-) was 66.67%, and Youden index was 0.677, respectively. The AUC of CTP score was 0.716, those of SN, SP, PV+, PV- and Youden index were 40.91%, 92.65%, 91.53%, 44.68% and 0.336, respectively. CONCLUSION: The LTS score is better than the CTP score in evaluating the prognosis of liver failure.

[Clinical value of Child-Turcotte-Pugh and model for end-stage liver disease score to predict the prognosis of chronic severe hepatitis].

OBJECTIVE: To compare the clinical value in predicting the prognosis of chronic severe hepatitis between the Child-Turcotte-Pugh (CTP) score and the model for end-stage liver disease (MELD) score. METHODS: Fifty-five cases with chronic severe hepatitis were scored by CTP and MELD score systems based on their biochemical and coagulation parameters, and related signs within 24 hours after their admission. The termination date of observation was the 90th day after their admission. The actual survival time were recorded. The comparison scores of CTP/MELD were conducted respectively and compared between the survival group and death group, among different clinical stages of chronic severe hepatitis. The correlation of CTP/MELD score with the clinical stages was analyzed respectively. The survival time, mortality and survival rate were compared respectively among the groups classified by CTP/MELD score according to Kaplan-Meier (K-M) survival curve. RESULTS: The CTP score and the MELD score in death group were higher than those in survival group (both P<0.01). The CTP and MELD scores in the advanced stage group were also higher than those in the early and middle stage (both P<0.01). The correlation of the MELD score with the stage was higher (r(s) =0.689,P<0.01) than that of the CTP score (r(s)=0.428, P<0.01). The survival time of patients with CTP<12 scores, was longer than with CTP>or=12 scores, and their survival rate was also higher(both P<0.01). When the MELD score lowered, survival time was longer, and survival rate was higher. The survival time, mortality and survival rate showed significant difference among the groups classified by MELD score (or=40 points, all P<0.01). CONCLUSION: The parameters employed in MELD score system are more OBJECTIVE: and easy to achieve, the score range for patients classification is wider and more practical, and the correlation with the clinical stage is higher than CTP score system, suggesting the MELD score system is better in predicting the prognosis of patients with chronic severe hepatitis than the CTP score system.