Distinct Lipidomic Profiles between People Living with HIV Treated with E/C/F/TAF or B/F/TAF: An Open-Label Prospective Cohort Study.

INTRODUCTION: Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) has been increasingly replaced by bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in the treatment of human immunodeficiency virus (HIV) owing to its more favorable pharmacokinetics and fewer drug-drug interactions. However, the effect of this switch on plasma lipids and lipidomic profiles remains poorly characterized. METHODS: HIV infected patients on an E/C/F/TAF regimen were recruited into the study and followed up every 12 weeks. Participants were divided into E/C/F/TAF and B/F/TAF groups depending on whether they were switched to B/F/TAF during follow-up. Clinical information and blood samples were collected at 0, 12, and 24 weeks, and lipidomic analysis was performed using liquid chromatography mass spectrometry. RESULTS: No significant differences were observed between the groups at baseline. At week 24, patients switched to B/F/TAF had lower triglyceride [mmol/L; 1.23 (0.62) versus 2.03 (0.75), P = 0.001] and very low-density lipoprotein cholesterol [mmol/L; 0.64 (0.26) versus 0.84 (0.32), P = 0.037) compared with patients who continued E/C/F/TAF therapy. Small decrease from baseline in Framingham general cardiovascular risk score (FRS) was observed in the B/F/TAF arm [week (W) 0: 2.59 (1.57) versus W24: 2.18 (1.01), P = 0.043]. Lipidomic analysis indicated that E/C/F/TAF treatment increased the levels of several diglycerides (DGs), triacylglycerols (TAGs), and lyso-phosphatidylcholines (LPCs), whereas switching to B/F/TAF led to increased sphingolipids and glycerophospholipids. After adjusting for demographic and clinical parameters, only DG (16:0/18:2), DG (18:2/22:6), DG (18:3/18:2), DG (20:5/18:2), TAG (18:3/18:2/21:5), TAG (20:5/18:2/22:6), and LPC (22:6) were found to be significantly associated with FRS (regression coefficient of 0.17-6.02, P < 0.05). Most of these FRS associate lipid species were significantly elevated in individuals treated with E/C/F/TAF instead of individuals treated with B/F/TAF. CONCLUSION: E/C/F/TAF promotes the accumulation of lipid species closely associated with cardiovascular disease (CVD) risk among people living with HIV, whereas B/F/TAF has a decreased impact on CVD-related lipid profile and is associated with lower CVD risk. A graphical abstract is available with this article. TRIAL REGISTRATION: ClinicalTrials.gov; identifier, NCT06019273.

Diagnostic Value of Metagenomic Next-Generation Sequencing for Multi-Pathogenic Pneumonia in HIV-Infected Patients.

Background: To evaluate the value and challenges of real-world clinical application of metagenomic next-generation sequencing (mNGS) for bronchoalveolar lavage fluid (BALF) in HIV-infected patients with suspected multi-pathogenic pneumonia. Methods: Fifty-seven HIV-infected patients with suspected mixed pneumonia who were agreed to undergo the bronchoscopy were recruited and retrospectively reviewed the results of mNGS and conventional microbiological tests (CMTs) of BALF from July 2020 to June 2022. Results: 54 patients were diagnosed with pneumonia including 49 patients with definite pathogens and five patients with probable pathogens. mNGS exhibited a higher diagnostic accuracy for fungal detection than CMTs in HIV-infected patients with suspected pulmonary infection. The sensitivity of mNGS in diagnosis of pneumonia in HIV-infected patients was much higher than that of CMTs (79.6% vs 61.1%; P < 0.05). Patients with mixed infection had lower CD4 T-cell count and higher symptom duration before admitting to the hospital than those with single infection. The detection rate of mNGS for mixed infection was significantly higher than that of CMTs and more co-pathogens could be identified by mNGS. The most common pattern of mixed infection observed was fungi-virus (11/29, 37.9%), followed by fungi-virus-bacteria (6/29, 20.7%) coinfection in HIV-infected patients with multi-pathogenic pneumonia. Conclusion: mNGS improved the pathogens detection rate and exhibited advantages in identifying multi-pathogenic pneumonia in HIV-infected patients. Early performance of bronchoscopy and mNGS are recommended in HIV-infected patients with low CD4 T cell counts and long duration of symptoms. The most common pattern of mixed infection observed was fungi-virus, followed by fungi-virus-bacteria coinfection in HIV infected patients with multi-pathogenic pneumonia.

Attention-aided lightweight networks friendly to smart weeding robot hardware resources for crops and weeds semantic segmentation.

Weed control is a global issue of great concern, and smart weeding robots equipped with advanced vision algorithms can perform efficient and precise weed control. Furthermore, the application of smart weeding robots has great potential for building environmentally friendly agriculture and saving human and material resources. However, most networks used in intelligent weeding robots tend to solely prioritize enhancing segmentation accuracy, disregarding the hardware constraints of embedded devices. Moreover, generalized lightweight networks are unsuitable for crop and weed segmentation tasks. Therefore, we propose an Attention-aided lightweight network for crop and weed semantic segmentation. The proposed network has a parameter count of 0.11M, Floating-point Operations count of 0.24G. Our network is based on an encoder and decoder structure, incorporating attention module to ensures both fast inference speed and accurate segmentation while utilizing fewer hardware resources. The dual attention block is employed to explore the potential relationships within the dataset, providing powerful regularization and enhancing the generalization ability of the attention mechanism, it also facilitates information integration between channels. To enhance the local and global semantic information acquisition and interaction, we utilize the refinement dilated conv block instead of 2D convolution within the deep network. This substitution effectively reduces the number and complexity of network parameters and improves the computation rate. To preserve spatial information, we introduce the spatial connectivity attention block. This block not only acquires more precise spatial information but also utilizes shared weight convolution to handle multi-stage feature maps, thereby further reducing network complexity. The segmentation performance of the proposed network is evaluated on three publicly available datasets: the BoniRob dataset, the Rice Seeding dataset, and the WeedMap dataset. Additionally, we measure the inference time and Frame Per Second on the NVIDIA Jetson Xavier NX embedded system, the results are 18.14 msec and 55.1 FPS. Experimental results demonstrate that our network maintains better inference speed on resource-constrained embedded systems and has competitive segmentation performance.

Case report: Ruxolitinib as first-line therapy for secondary hemophagocytic lymphohistiocytosis in patients with AIDS.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a fatal immunological syndrome resulting from excessive production of inflammatory cytokines. The conventional therapies for HLH, which are based on cytotoxic agents, are not always efficacious and safe, especially in patients with severe immunodeficiency. Ruxolitinib, a strong inhibitor of Janus kinase (JAK) 1/2, has already been evaluated as salvage and first-line therapy for HLH. Despite its promising efficacy and tolerability in the treatment of secondary HLH, the efficacy and safety of ruxolitinib in HLH patients with HIV infection remain to be investigated. Case presentation: Two men (ages: 45 and 58 years) both presented at our hospital with a high fever. They were found to be HIV-positive with severe immunodeficiency and opportunistic infections. Their laboratory tests showed severe pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and increased levels of inflammatory factors and ferritin. Hemophagocytosis was found in the bone marrow, and abdominal computed tomography or ultrasonography showed splenomegaly. Both patients were diagnosed with infection-induced HLH due to severe immunodeficiency. Given they were both highly immunocompromised, we chose ruxolitinib as a first-line treatment alternative to cytotoxic chemotherapy. Rapid remission of clinical symptoms and normalization of laboratory parameters were achieved after ruxolitinib therapy. Neither patient had any associated adverse drug reactions or other laboratory abnormalities. Both patients were eventually discharged and ruxolitinib was discontinued as their disease alleviated, and they did not show signs of relapse during the 3- and 5-month of follow-up examinations. Conclusion: We described two cases of AIDS-related secondary HLH treated with ruxolitinib. Our cases highlight the feasibility of using ruxolitinib as a first-line therapy in patients with HIV infection and secondary HLH. Nevertheless, the safety and efficacy of this novel treatment need to be evaluated in large clinical trials in the future.

HBV Facilitated Hepatocellular Carcinoma Cells Proliferation by Up-Regulating Angiogenin Expression Through IL-6.

BACKGROUND/AIMS: Patients with hepatitis B virus (HBV) infection are at a high risk of developing hepatocellular carcinoma (HCC). In this study, we aim to investigate the roles of HBV on angiogenin (ANG), as well as the effects on cell proliferation in presence of ANG down-regulation. METHODS: Serum ANG was determined by ELISA. The expression of ANG mRNA and protein in HCC cell lines with or without HBV/HBx were determined. Western blot and ELISA were conducted to determine the effects of HBV/HBx on IL-6 expression. The role of IL-6 on ANG was evaluated by IL-6 recombinant protein or IL-6 neutralizing antibody. Immunofluorescence staining was used to detect the nuclear translocation of ANG. MTT was performed to evaluate the relative inhibition ratio. RESULT: In vivo experiments showed elevation of serum ANG in patients infected with HBV. In vitro experiments showed HBV and HBx contributed to the transcription and translation of ANG. ANG expression showed increase after IL-6 stimulation, and ANG protein decreased in the presence of IL-6 blocking with its antibody. HBV promoted nuclear translocation of ANG. Inhibiting ANG expression or blocking of nuclear transfer of ANG attenuated the 45S rRNA synthesis and cell proliferation. CONCLUSION: HBV and HBx protein can increase the level of ANG through IL-6. HBV and HBx contributed to the nuclear translocation of ANG. Cell proliferation was inhibited after inhibiting the expression or nuclear transfer of ANG.

MEAN inhibits hepatitis C virus replication by interfering with a polypyrimidine tract-binding protein.

MEAN (6-methoxyethylamino-numonafide) is a small molecule compound, and here, we report that it effectively inhibits hepatitis C virus (HCV) infection in an HCV cell culture system using a JC1-Luc chimeric virus, with a 50% effective concentration (EC50) of 2.36 ± 0.29 µM. Drug combination usage analyses demonstrated that MEAN was synergistic with interferon α, ITX5061 and ribavirin. In addition, MEAN effectively inhibits N415D mutant virus and G451R mutant viral infections. Mechanistic studies show that the treatment of HCV-infected hepatocytes with MEAN inhibits HCV replication but not translation. Furthermore, treatment with MEAN significantly reduces polypyrimidine tract-binding protein (PTB) levels and blocks the cytoplasmic redistribution of PTB upon infection. In the host cytoplasm, PTB is directly associated with HCV replication, and the inhibition of HCV replication by MEAN can result in the sequestration of PTB in treated nuclei. Taken together, these results indicate that MEAN is a potential therapeutic candidate for HCV infection, and the targeting of the nucleo-cytoplasmic translocation of the host PTB protein could be a novel strategy to interrupt HCV replication.

Lipocalin 2 Upregulation Protects Hepatocytes from IL1-ß-Induced Stress.

BACKGROUND: Lipocalin 2 (LCN2), a protein primarily produced by hepatocytes, is highly upregulated under various conditions that induce cellular stress, such as intoxication, infection or inflammation. However, the precise biological functions and underlying mechanisms of LCN2 in hepatocytes remains unknown. METHODS: Hepatocyte stress was successfully induced by treating Huh7 cells with interleukin-1ß (IL-1ß). Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α) and LCN2 levels were measured in IL-1ß treated Huh7 cells and supernatant. Additionally, microarray analysis was conducted to identify genes differentially expressed in LCN2-silenced and control Huh7 cells. RESULTS: TNF-α, IL-6 and LCN2 were significantly elevated in Huh7 cells after IL-1ß) treatment. In LCN2-silenced Huh7 cells, expression of IL-6 and TNF-α was significantly increased when compared with the expression levels of control Huh7 cells. Furthermore, differentially expressed genes were observed between the LCN2-silenced and control cells. Microarray analysis indicated that LCN2 acted by influencing genes involved in protein metabolism, stress response, cell cycle and proliferation. CONCLUSIONS: Our results suggest that LCN2 upregulation protects hepatocytes from IL-1ß-induced stress. Additionally, our microarray analysis of LCN2-silenced and control cells provides a better understanding of the mechanisms that may be influenced by LCN2 induction.

MicroRNA-223 acts as an important regulator to Kupffer cells activation at the early stage of Con A-induced acute liver failure via AIM2 signaling pathway.

BACKGROUND: Acute liver failure (ALF), known as a rapid and severe clinical syndrome, can induce multiple organ dysfunction and failure. It was noticed that Kupffer cells activation at the initial phase was involved in some intense inflammatory responses in the pathogenesis of ALF. However, detailed regulation mechanism of Kupffer cells activation during ALF is still obscured. Present study aimed to discover the potential regulator and explore deeper information of Kupffer cells activation at the early stage of ALF. METHODS: The mouse model of ALF was established by Concanavalin A injection. Dynamic immunological statuses of Kupffer cells at the early stage of ALF were exhibited by detecting typical cytokines. The expression of inflammasome AIM2 was measured in both RNA and protein level. Its role of affecting Kupffer cells activation during ALF by inducing IL-1ß production was identified by RNA interference in vitro. Moreover, the expression of miR-223 in vivo was measured by q-PCR and its role in regulating Kupffer cells activation during Con A induced ALF was determined by RNAs transfection. RESULTS: Present study showed that mass production of IL-1ß from isolated Kupffer cells in Con A treated mice might be the main driving force of Kupffer cells pro-inflammatory activation during ALF. The role of AIM2 in affecting pro-inflammatory activation of Kupffer cells by inducing IL-1ß production was crucial to ALF. Further study found that miR-223 acted as a regulator in Kupffer cells activation at the early stage of ALF by influencing IL-1ß production via AIM2 pathway. CONCLUSION: For the first time, this paper demonstrated that miR-223 acted to inhibit IL-1ß production via AIM2 pathway, suppressing Kupffer cells pro-inflammatory activation at the early stage of ALF. Thus, it played an important role in the pathogenesis of ALF.

[Design and in vitro evaluation of self-microemulsifying drug delivery systems for piroxicam].

Self-microemulsifying drug delivery systems (SMEDDS) were developed to overcome the problems of delivery and administration of piroxicam, a drug with low bioavailability and gastrointestinal irritation, The in vitro properties of it were assessed. The solubility of piroxicam in several oils and surfactants was determined, and the compatibility of various oils and surfactants was investigated. Ternary phase diagrams were constructed to optimal area of microemulsion, and the influence of different oily phases, surfactants and co-surfactants was studied. The droplet size and dissolution of optimal formulation were determined to prove that the dosage form is a useful delivery system for piroxicam. In the optimized piroxicam SMEDDS, cinnamic alcohol was selected that gave the maximal solubility to piroxicam. Labrafil M 1944CS, Cremophor EL and Transcotol P were used as oils, surfactant and co-surfactant, respectively. Droplet size and distribution of three piroxicam SMEDDS formulations were (32.2 +/- 5.0), (40.1 +/- 6.4), (81.9 +/- 12.2) nm individually. And the releasing of piroxicam was rapid and complete. The optimized SMEDDS for piroxicam was obtained.