Effectiveness of integrase strand transfer inhibitors among treatment-naive people living with HIV/AIDS in Guangdong, China: A real-world, retrospective cohort study.

Integrase strand transfer inhibitors (INSTIs) in anti-retroviral therapy (ART) have been recommended by the World Health Organization for their higher efficacy, favorable safety and tolerability. However, the clinical evidence supporting switching to INSTI-containing regimens in low-and-middle-income countries (LMICs) is limited, as few patients have access to these regimens. We aimed to assess the effectiveness of INSTI-containing regimens in real-world settings in China compared to government-provided free ART. We compared the short-term (first 4 mo following ART initiation) and long-term (1 year after ART initiation) effectiveness between INSTI-containing regimens and free ART drugs provided by the Chinese government in 4 dimensions: viral suppression status, immune response, liver and kidney function, and AIDS-related diseases. We obtained data from electronic medical records in the National Infectious Disease Surveillance System. To control baseline confounders, we used propensity score matching (PSM), calculated using logistic regression including socio-demographic and baseline factors. Among 12,836 patients from 2012 to 2019, 673 (5.2%) used INSTI-containing regimens. Patients with INSTI-containing regimens were matched to those with free drugs (644 vs 644). For short-term effectiveness, patients initiating INSTI-containing regimens were more likely to achieve viral suppression (81.4% vs 52.0%; P < .001). The differences in immune response, liver and kidney function and AIDS-related diseases were not significant between the 2 groups. For long-term effectiveness, viral suppression rates were similar (87.96% vs 84.59%; P = .135), with no significant differences in immune response, liver and kidney function, or AIDS-related diseases. Our study suggests that patients initiating ART with INSTI-containing regimens have worse physical status at baseline than patients starting with free ART drugs. Furthermore, we found better virological performances of INSTI-containing regimens in the short-term but not in the long-term due to a high rate of drug changes. Our findings have clinical implications and provide new evidence regarding the effectiveness of INSTI-containing regimens in LMICs.

Early on-treatment plasma interleukin-18 as a promising indicator for long-term virological response in patients with HIV-1 infection.

Background and aims: It is necessary to identify simple biomarkers that can efficiently predict the efficacy of long-term antiretroviral therapy (ART) against human immunodeficiency virus (HIV), especially in underdeveloped countries. We characterized the dynamic changes in plasma interleukin-18 (IL-18) and assessed its performance as a predictor of long-term virological response. Methods: This was a retrospective cohort study of HIV-1-infected patients enrolled in a randomized controlled trial with a follow-up of 144 weeks of ART. Enzyme-linked immunosorbent assay was performed to evaluate plasma IL-18. Long-term virological response was defined as HIV-1 RNA <20 copies/mL at week 144. Results: Among the 173 enrolled patients, the long-term virological response rate was 93.1%. Patients with a long-term virological response had significantly lower levels of week 24 IL-18 than non-responders. We defined 64 pg./mL, with a maximum sum of sensitivity and specificity, as the optimal cutoff value of week 24 IL-18 level to predict long-term virological response. After adjusting for age, gender, baseline CD4+ T-cell count, baseline CD4/CD8 ratio, baseline HIV-1 RNA level, HIV-1 genotype and treatment strategy, we found that lower week 24 IL-18 level (≤64 vs. >64 pg./mL, a OR 19.10, 95% CI: 2.36-154.80) was the only independent predictor of long-term virological response. Conclusion: Early on-treatment plasma IL-18 could act as a promising indicator for long-term virological response in patients with HIV-1 infection. Chronic immune activation and inflammation may represent a potential mechanism; further validation is necessary.

Combining Cryo-Thermal Therapy with Anti-IL-6 Treatment Promoted the Maturation of MDSCs to Induce Long-Term Survival in a Mouse Model of Breast Cancer.

Immunosuppression plays a significant role in tumor recurrence and metastasis, ultimately causing poor survival outcomes. Overcoming immunosuppression and stimulating durable antitumor immunity are essential for tumor treatment. In our previous study, a novel cryo-thermal therapy involving liquid nitrogen freezing and radiofrequency heating could reduce the proportion of Myeloid-derived suppressor cells (MDSCs), but the remaining MDSCs produced IL-6 by the NF-κB pathway, resulting in an impaired therapeutic effect. Therefore, here we combined cryo-thermal therapy with anti-IL-6 treatment to target the MDSC-dominant immunosuppressive environment, thereby optimizing the efficacy of cryo-thermal therapy. We found that combinational treatment significantly increased the long-term survival rate of breast cancer-bearing mice. Mechanistic investigation revealed that combination therapy was capable of reducing the proportion of MDSCs in the spleen and blood while promoting their maturation, which resulted in increased Th1-dominant CD4+ T-cell differentiation and enhancement of CD8+ T-mediated tumor killing. In addition, CD4+ Th1 cells promoted mature MDSCs to produce IL-7 through IFN-γ, indirectly contributing to the maintenance of Th1-dominant antitumor immunity in a positive feedback loop. Our work suggests an attractive immunotherapeutic strategy targeting the MDSC-dominant immunosuppressive environment, which would offer exciting opportunities for highly immunosuppressive and unresectable tumors in the clinic.

Unbalance between working memory task-activation and task-deactivation networks in epilepsy: Simultaneous EEG-fMRI study.

Working memory (WM) is a cognitive function involving emergent properties of theta oscillations and large-scale network interactions. The synchronization of WM task-related networks in the brain enhanced WM performance. However, how these networks regulate WM processing is not well known, and the alteration of the interaction among these networks may play an important role in patients with cognitive dysfunction. In this study, we used simultaneous EEG-fMRI to examine the features of theta oscillations and the functional interactions among activation/deactivation networks during the n-back WM task in patients with idiopathic generalized epilepsy (IGE). The results showed that there was more enhancement of frontal theta power along with WM load increase in IGE, and the theta power was positively correlated with the accuracy of the WM tasks. Moreover, fMRI activations/deactivations correlated with n-back tasks were estimated, and we found that the IGE group had increased and widespread activations in high-load WM tasks, including the frontoparietal activation network and task-related deactivation areas, such as the default mode network and primary visual and auditory networks. In addition, the network connectivity results demonstrated decreased counteraction between the activation network and deactivation network, and the counteraction was correlated with the higher theta power in IGE. These results indicated the important role of the interactions between activation and deactivation networks during the WM process, and the unbalance among them may indicate the pathophysiological mechanism of cognitive dysfunction in generalized epilepsy.

Adherence to Antiretroviral Therapy and Its Predictive Factors Among People Living with HIV in China: A Behavioral Theory-Based Prospective Cohort Study.

BACKGROUND: Free antiretroviral therapy (ART) has been expanded to all people living with HIV (PLWH) in China since 2016, and adherence to ART has been shown to be the primary determinant of viral suppression. This study aimed to investigate the ART adherence and its associated factors among PLWH in China in the context of a scaling-up of treatment policy. METHOD: A prospective cohort study was conducted from June 2016 to May 2018 in Guangzhou, China. A total of 400 eligible participants were recruited from the Guangzhou Eighth People's hospital in Guangzhou, China. The Theory of Planned Behavior and the Behavioral Maintenance Theory were applied to guide the questionnaire design. Participants were invited to completed self-administered questionnaire at baseline and months 3 and 6 post-baseline. Logistic regression models were fitted to explore factors associated with ART adherence. RESULTS: Of the 400 participants, the prevalence of optimal ART adherence was 83.6% at month 3 and 83.3% at month 6. The baseline attitude (ORa = 1.11, P < 0.05), behavioral intention (ORa = 1.90, P < 0.05), and outcome expectations (ORa = 1.09, P < 0.001) predicted ART adherence at month 3 in adjusted analyses, but only outcome expectations (ORa = 1.09, P < 0.01) remained significant in the final multivariate model. At month 3, negative experiences (ORa = 0.62, P < 0.05) were the only predictor of adherence at month 6. CONCLUSION: Approximately 15% of participants reported suboptimal ART adherence. The developments of tailored interventions that target factors such as outcome expectations at baseline and negative experiences during treatment are warranted.

Activated NK cells reprogram MDSCs via NKG2D-NKG2DL and IFN-γ to modulate antitumor T-cell response after cryo-thermal therapy.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) can potently inhibit T-cell activity, promote growth and metastasis of tumor and contribute to resistance to immunotherapy. Targeting MDSCs to alleviate their protumor functions and immunosuppressive activities is intimately associated with cancer immunotherapy. Natural killer (NK) cells can engage in crosstalk with multiple myeloid cells to alter adaptive immune responses, triggering T-cell immunity. However, whether the NK-cell-MDSC interaction can modulate the T-cell immune response requires further study. Cryo-thermal therapy could induce the maturation of MDSCs by creating an acute inflammatory environment to elicit a CD4+ Th1-dominant immune response, but the mechanism regulating this process remains unclear. METHODS: NK cells were depleted and NKG2D was blocked with monoclonal antibodies in vivo. MDSCs, NK cells and T cells were assessed by flow cytometry and isolated by magnetic-activated cell sorting (MACS). MDSCs and NK cells were cocultured with T cells to determine their immunological function. The transcriptional profiles of MDSCs were measured by qRT-PCR and RNA-sequencing. Isolated NK cells and MDSCs by MACS were cocultured to study the viability and maturation of MDSCs regulated by NK cells. TIMER was used to comprehensively examine the immunological, clinical, and genomic features of tumors. RESULTS: NK-cell activation after cryo-thermal therapy decreased MDSC accumulation and reprogrammed immunosuppressive MDSCs toward a mature phenotype to promote T cell antitumor immunity. Furthermore, we discovered that NK cells could kill MDSCs via the NKG2D-NKG2DL axis and promote MDSC maturation by interferon gamma (IFN-γ) in response to NKG2D. In addition, CD4+ Th1-dominant antitumor immune response was dependent on NKG2D, which promoted the major histocompatibility complex Ⅱ pathway of MDSCs. High activated NK-cell infiltration and NKG2D level in tumors were positively correlated with better clinical outcomes. CONCLUSIONS: Cryo-thermal therapy induces effective CD4+ Th1-dominant antitumor immunity by activating NK cells to reprogram MDSCs, providing a promising therapeutic strategy for cancer immunotherapy.

Combining all-trans retinoid acid treatment targeting myeloid-derived suppressive cells with cryo-thermal therapy enhances antitumor immunity in breast cancer.

Targeting myeloid-derived suppressive cells (MDSCs) has been considered a potential strategy in tumor therapy. However, a single drug targeting MDSCs remains a challenge in the clinic. An increasing number of studies have shown that combination agents targeting MDSCs and immunotherapy may provide exciting new insights and avenues to explore in tumor therapy. In our previous study, a novel cryo-thermal therapy was developed for metastatic tumors that systematically activate innate and adaptive immunity. Moreover, cryo-thermal therapy was shown to dramatically decrease the levels of MDSCs and induce their differentiation toward potent antigen-presenting cells. However, the therapeutic effects of cryo-thermal therapy on the 4T1 mouse breast cancer model were still not satisfactory because of the high level of MDSCs before and after treatment. Therefore, in this study, we combined cryo-thermal therapy with all-trans retinoid acid (ATRA), a small molecule drug that can induce the inflammatory differentiation of MDSCs. We found that combination therapy notably upregulated the long-term survival rate of mice. Mechanically, combination therapy promoted the phenotype and functional maturation of MDSCs, efficiently decreasing suppressive molecule expression and inhibiting glutamine and fatty acid metabolism. Moreover, MDSCs at an early stage after combination therapy significantly decreased the proportions of Th2 and Treg subsets, which eventually resulted in Th1-dominant CD4+ T-cell differentiation, as well as enhanced cytotoxicity of CD8+ T cells and natural killer cells at the late stage. This study suggests a potential therapeutic strategy for combination ATRA treatment targeting MDSCs with cryo-thermal therapy to overcome the resistance of MDSC-induced immunosuppression in the clinic.

HIV-infected patients rarely develop invasive fungal diseases under good immune reconstitution after ART regardless high prevalence of pathogenic filamentous fungi carriage in nasopharynx/oropharynx.

Purpose: We aimed to investigate the prevalence and risk factors of filamentous fungi (FF) carriage in human immunodeficiency virus (HIV)-infected patients in Guangdong province, along with its subsequent incidence of invasive fungal disease (IFD). Methods: Seven hundred and sixteen HIV-infected individuals from the outpatient clinic and 293 sex-matched healthy controls were recruited prospectively from May 1 to August 31, 2017. Fungi were isolated from oropharyngeal and nasopharyngeal swabs, then identified by morphological and molecular biological techniques. Logistic regression analysis was used to identify risk factors of pathogenic FF carriage. Pathogenic FF carriers were followed up through the end of 2019. Results: Of the 716 included HIV-infected patients, 602 (84.1%) were male, the median age was 34 (27-42) years, and the median CD4+ count was 385 (254-542) cells/µl. Pathogenic FF were isolated in 119 (16.6%) cases with HIV infection and 40 (13.7%) healthy controls. Mucorales were found in 3 HIV-infected individuals and Talaromyces marneffei in 2 HIV-infected individuals, but not in healthy controls. History of cured opportunistic infections (OIs; OR, 1.97; 95% CI, 1.23-3.13, p = 0.004), and smoking (OR, 1.55; 95%CI, 1.03-2.32, p = 0.035) were independent risk factors of pathogenic FF carriage in HIV-infected individuals. A total of 119 pathogenic FF carriers with HIV infection were followed. During follow-up, 119 (100%) cases received antiretroviral therapy (ART) for at least 28 months, 107 (90%) cases had CD4+ counts>200 cells/µl, and none developed IFD. Discussion: Pathogenic FF carriage is common in HIV-infected individuals but may not develop IFD in those who achieved immune reconstitution. Smoking and cured OIs history increase the risk of pathogenic FF carriage. Smoking abstinence and ART adherence are especially important for these patients.

Baseline and Process Factors of Anti-Retroviral Therapy That Predict Loss to Follow-up Among People Living with HIV/AIDS in China: A Retrospective Cohort Study.

We explored the predictors and predictive models of loss to follow-up (LTFU) during the first year of anti-retroviral therapy (ART). LTFU was defined as the failure to visit the clinic for antiretroviral drugs for ≥ 90 days after the last missed scheduled visit. Based on the electronic medical records of 5953 patients who were HIV positive and began ART between 2016 and 2019 in China, the LTFU rate was 7.24 (95% confidence interval 6.49-7.97) per 100 person-years during the first year of ART. ART baseline factors were associated with LTFU, but were non-optimal predictors. A model including ART process-related factors such as follow-up behaviors and physical health status had an area under the receiver operating characteristic curve of 73.4% for predicting LTFU. Therefore, the medical records of follow-up visits can be used to identify patients with a high risk of LTFU and allow interventions to be implemented proactively.

Alcohol use among patients with epilepsy in western China. A hospital-based study.

AMIS: Alcohol consumption has multiple negative consequences for people with epilepsy, including precipitation of seizure or status epilepticus, worsening of seizure control, increased adverse effects of anti-seizure medications, increased sudden unexpected death in epilepsy, and premature mortality. The aim of this study was to investigate alcohol use and explore the sociodemographic and clinical factors associated with alcohol use among patients with epilepsy in western China. METHODS: A face-to-face questionnaire on alcohol use was conducted at Sichuan Provincial People's Hospital from December 2020 to June 2021. All adult patients who came to our epilepsy center (inpatient and outpatient) were invited to participate in this study. Logistic regression was used to evaluate the possible risk factors associated with alcohol use within the last 12 months. RESULTS: A total of 425 patients completed this study, 24.2% of patients with epilepsy had used alcohol within the last 12 months, being male and having a history of alcohol use were independently associated factors. Among patients who had used alcohol within the last 12 months, 52.4% complained of worsening of seizure control, heavy alcohol use, and frequent alcohol use were independently associated with worsening of seizure control after alcohol use in patients with epilepsy. CONCLUSION: This study revealed that the rate of alcohol use among patients with epilepsy was high. Male patients with a history of alcohol use were more prone to alcohol use after a diagnosis of epilepsy. Heavy alcohol use and frequent alcohol use were independently associated with worsening of seizure control after alcohol use in patients with epilepsy. Patient education on the destructive effects of alcohol use is needed for patients with epilepsy.

Metformin regulates the Th17/Treg balance by glycolysis with TIGAR in hepatic ischemia-reperfusion injury.

The balance of Th17/Treg plays an important role in hepatic ischemia-reperfusion (I/R) injury. Glycolysis and glutaminolysis for energy metabolism governs the differentiate of CD 4+ T-cells to Th17/Treg. Metformin can regulate glucose metabolism in the liver, but its protective effect on I/R liver injury and its effect on Th17/Treg balancestill unknown. In this study, the I/R liver injury rat model and the primary hepatocyte hypoxia/reoxygenation injury model were established. The biochemical indexes, inflammatory factor indexes, Th17/Treg balance and energy metabolism were evaluated. RNA-seq and gene knockout cells were used to investigated the target protein of metformin. The results showed that metformin could effectively improve liver injury caused by I/R, significantly inhibit the glycolysis, improve the Th17/Treg balance, and inhibit the expression of inflammatory factors. RNA-seq results showed that TIGAR was a possible regulatory site of metformin. However, the protective effect and the regulating effect of Th17/Treg balance by metformin in TIGAR knock-out cells were disappeared. In conclusion, metformin could regulate TIGAR inhibit glycolysis then regulate Th17/Treg balance, inhibit the release of liver inflammatory factors, and finally play a role in inhibiting the occurrence of liver injury caused by ischemia-reperfusion.

Identifying Refractory Epilepsy Without Structural Abnormalities by Fusing the Common Spatial Patterns of Functional and Effective EEG Networks.

Drug refractory epilepsy (RE) is believed to be associated with structural lesions, but some RE patients show no significant structural abnormalities (RE-no-SA) on conventional magnetic resonance imaging scans. Since most of the medically controlled epilepsy (MCE) patients also do not exhibit structural abnormalities, a reliable assessment needs to be developed to differentiate RE-no-SA patients and MCE patients to avoid misdiagnosis and inappropriate treatment. Using resting-state scalp electroencephalogram (EEG) datasets, we extracted the spatial pattern of network (SPN) features from the functional and effective EEG networks of both RE-no-SA patients and MCE patients. Compared to the performance of traditional resting-state EEG network properties, the SPN features exhibited remarkable superiority in classifying these two groups of epilepsy patients, and accuracy values of 90.00% and 80.00% were obtained for the SPN features of the functional and effective EEG networks, respectively. By further fusing the SPN features of functional and effective networks, we demonstrated that the highest accuracy value of 96.67% could be reached, with a sensitivity of 100% and specificity of 92.86%. Overall, these findings not only indicate that the fused functional and effective SPN features are promising as reliable measurements for distinguishing RE-no-SA patients and MCE patients but also may provide a new perspective to explore the complex neurophysiology of refractory epilepsy.

Antiretroviral Long-Term Efficacy and Resistance of Lopinavir/Ritonavir Plus Lamivudine in HIV-1-Infected Treatment-Naïve Patients (ALTERLL): 144-Week Results of a Randomized, Open-Label, Non-Inferiority Study From Guangdong, China.

Dual therapy with lopinavir/ritonavir (LPV/r) plus lamivudine (3TC) has been demonstrated to be non-inferior to the triple drug regimen including LPV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) in 48-week studies. However, little is known about the long-term efficacy and drug resistance of this simplified strategy. A randomized, controlled, open-label, non-inferiority trial (ALTERLL) was conducted to assess the efficacy, drug resistance, and safety of dual therapy with LPV/r plus 3TC (DT group), compared with the first-line triple-therapy regimen containing tenofovir (TDF), 3TC plus efavirenz (EFV) (TT group) in antiretroviral therapy (ART)-naïve HIV-1-infected adults in Guangdong, China. The primary endpoint was the proportion of patients with plasma HIV-1 RNA < 50 copies/ml at week 144. Between March 1 and December 31, 2015, a total of 196 patients (from 274 patients screened) were included and randomly assigned to either the DT group (n = 99) or the TT group (n = 97). In the primary intention-to-treat (ITT) analysis at week 144, 95 patients (96%) in the DT group and 93 patients (95.9%) in the TT group achieved virological inhibition with plasma HIV-1 RNA <50 copies/ml (difference: 0.1%; 95% CI, -4.6-4.7%), meeting the criteria for non-inferiority. The DT group did not show significant differences in the mean increase in CD4+ cell count (247.0 vs. 204.5 cells/mm3; p = 0.074) or the CD4/CD8 ratio (0.47 vs. 0.49; p = 0.947) from baseline, or the inflammatory biomarker levels through week 144 compared with the TT group. For the subgroup analysis, baseline high viremia (HIV-1 RNA > 100,000 copies/ml) and genotype BC did not affect the primary endpoint or the mean increase in CD4+ cell count or CD4/CD8 ratio from baseline at week 144. However, in patients with genotype AE, the DT group showed a higher mean increase in CD4+ cell count from baseline through 144 weeks than the TT group (308.7 vs. 209.4 cells/mm3; p = 0.038). No secondary HIV resistance was observed in either group. Moreover, no severe adverse event (SAE) or death was observed in any group. Nonetheless, more patients in the TT group (6.1%) discontinued the assigned regimen than those in the DT group (1%) due to adverse events. Dual therapy with LPV/r plus 3TC manifests long-term non-inferior therapeutic efficacy, low drug resistance, good safety, and tolerability compared with the first-line triple-therapy regimen in Guangdong, China, indicating dual therapy is a viable alternative in resource-limited areas. Clinical Trial Registration: [http://www.chictr.org.cn], identifier [ChiCTR1900024611].

Time-Varying Networks of Inter-Ictal Discharging Reveal Epileptogenic Zone.

The neuronal synchronous discharging may cause an epileptic seizure. Currently, most of the studies conducted to investigate the mechanism of epilepsy are based on EEGs or functional magnetic resonance imaging (fMRI) recorded during the ictal discharging or the resting-state, and few studies have probed into the dynamic patterns during the inter-ictal discharging that are much easier to record in clinical applications. Here, we propose a time-varying network analysis based on adaptive directed transfer function to uncover the dynamic brain network patterns during the inter-ictal discharging. In addition, an algorithm based on the time-varying outflow of information derived from the network analysis is developed to detect the epileptogenic zone. The analysis performed revealed the time-varying network patterns during different stages of inter-ictal discharging; the epileptogenic zone was activated prior to the discharge onset then worked as the source to propagate the activity to other brain regions. Consistence between the epileptogenic zones detected by our proposed approach and the actual epileptogenic zones proved that time-varying network analysis could not only reveal the underlying neural mechanism of epilepsy, but also function as a useful tool in detecting the epileptogenic zone based on the EEGs in the inter-ictal discharging.