Increase in HIV reservoir and T cell immune response after CoronaVac vaccination in people living with HIV.

Introduction: CoronaVac, an inactivated vaccine developed by Sinovac Life Sciences, has been widely used for protection against Coronavirus Disease 2019 (COVID-19). This study investigates its effect on the HIV reservoir and T cell repertoires in people living with HIV (PLWHs). Methods: Blood samples were collected from fifteen PLWHs who were administered at least two doses of CoronaVac between April 2021 and February 2022. The levels of cell-associated HIV RNA (CA HIV RNA) and HIV DNA, as well as the T cell receptor (TCR) repertoire profiles, TCR clustering and TCRß annotation, were studied. Results: A significant increase was observed in CA HIV RNA at 2 weeks (431.5 ± 164.2 copies/106 cells, P = 0.039) and 12 weeks (330.2 ± 105.9 copies/106 cells, P = 0.019) after the second dose, when compared to the baseline (0 weeks) (73.6 ± 23.7 copies/106 cells). Various diversity indices of the TCRß repertoire, including Shannon index, Pielou's evenness index, and Hvj Index, revealed a slight increase (P < 0.05) following CoronaVac vaccination. The proportion of overlapping TCRß clonotypes increased from baseline (31.9 %) to 2 weeks (32.5 %) and 12 weeks (40.4 %) after the second dose. We also found that the breadth and depth of COVID-19-specific T cells increased from baseline (0.003 and 0.0035) to 12 weeks (0.0066 and 0.0058) post the second dose. Conclusions: Our study demonstrated an initial increase in HIV reservoir and TCR repertoire diversity, as well as an expansion in the depth and breadth of COVID-19-specific T-cell clones among CoronaVac-vaccinated PLWHs. These findings provide important insights into the effects of COVID-19 vaccination in PLWHs.

A potential antiviral role for CCR5+CD8+ T cells in children with hepatitis B.

While dysfunctional exhausted CD8+ T cells hamper viral control when children acquire hepatitis B virus (HBV) infection, it's crucial to recognize that CD8+ T cells have diverse phenotypes and functions. This study explored a subset of CD8+ T cells expressing C-C chemokine receptor type 5 (CCR5) in children with HBV infection. Thirty-six patients in the immune tolerant group, 33 patients in the immune active group, 55 patients in the combined response group, and 22 healthy control children were enrolled. The frequency, functional molecules, and effector functions of the CCR5+CD8+ T cell population in different groups were evaluated. The frequency of CCR5+CD8+ T cells correlated positively with the frequency of CCR5+CD4+ T cells and patient age, and it correlated negatively with alanine aminotransferase, aspartate transaminase, HBV DNA, hepatitis B surface antigen, and lactic dehydrogenase levels. CCR5+CD8+ T cells had higher levels of inhibitory and activated receptors and produced higher levels of IFN-γ, IL-2, and TNF-α than CCR5-CD8+ T cells. CCR5+CD8+ T cells were partially exhausted but possessed a stronger antiviral activity than CCR5-CD8+ T cells. The identification of this subset increases our understanding of CD8+ T cell functions and serves as a potential immunotherapeutic target for children with HBV infection.

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.

Postoperative SIRS after thermal ablation of HCC: Risk factors and short-term prognosis.

Background: We aimed to explore the potential risk factors and short-term prognosis for SIRS after thermal ablation of hepatocellular carcinoma (HCC). Methods: Data from patients with HCC who underwent thermal ablation in the Third Affiliated Hospital of Sun Yat-sen University between January 2015 and August 2021 were retrieved from the perioperative database. Pre-, intra- and postoperative data between SIRS group and non-SIRS group were compared and multivariate logistic regression analysis was performed to identify the risk factors for SIRS after thermal ablation. Results: A total of 1491 patients were enrolled and 234 (15.7 %) patients developed SIRS after thermal ablation. Compared with those without SIRS, patients with SIRS had a longer hospital stay, higher hospitalization costs and higher risk of more severe postoperative complications. In the multivariate logistic regression analysis, current smoking (OR 1.58, 95 %CI 1.09-2.29), decreased HCT (OR 1.51,95 %CI 1.11-2.04), NEUT < 1.5 × 109/L(OR 1.74, 95 %CI 1.14-2.65), NEUT% < 0.5 or > 0.7 (OR 1.36, 95 %CI 1.01-1.83) and PT > 16.3s (OR 2.42, 95 %CI 1.57-3.74) were significantly associated with postoperative SIRS. Conclusions: Current smoking, decreased HCT, neutropenia, abnormal percentage of neutrophils and prolonged PT are the independent risk factors for SIRS after thermal ablation of HCC, which worsens outcomes of patients. This study can help identify high-risk population and guide appropriate care so as to reduce the incidence of postoperative SIRS.

The central nervous system is a potential reservoir and possible origin of drug resistance in hepatitis B infection.

Background: The significance of hepatitis B virus (HBV) in cerebrospinal fluid (CSF) is unclear. Methods: Synchronous serum and CSF samples were collected from 13 patients. HBV DNA, full-length genome, quasispecies, phylogenetic tree, compartmentalization and mutation of the reverse transcriptase (RT) region were performed based on PCR and sequencing methods. Results: HBV DNA was detected in the CSF of 3 antiviral-naïve individuals and 1 individual after successful antiviral therapy. Complete full-length HBV genomes were isolated from the CSF of 5 individuals, including 2 with undetectable serum HBV DNA. Ten individuals exhibited distinct CSF-serum quasispecies, 8 harbored independent CSF-serum genetic compartmentalization and phylogenetic trees, and 5 lamivudine/entecavir-associated resistance mutations only in the CSF. The frequencies of rtL180M and rtM204I/V mutations in both serum and CSF were higher in HIV-HBV-coinfected individuals than in the HBV-monoinfected ones (serum: rtL180M: 3.9% vs. 0, P = 0.004; rtM204I/V: 21.3% vs. 0, P < 0.001; CSF: rtL180M: 7.6% vs. 0, P = 0.026; rtM204I/V 7.6% vs. 1.6%, P = 0.097). Conclusion: CSF is a potential HBV reservoir, and HBV in CSF harbors distinct evolution and mutation characteristics from those in serum. HIV infection increases the possibility of HBV rtL180M and rtM204I/V mutations in both serum and CSF.

Humoral immune responses to inactivated COVID-19 vaccine up to 1 year in children with chronic hepatitis B infection.

Background: Inactivated SARS-CoV-2 vaccination has recently been approved for children aged 3-17 years in China. However, data on long-term humoral responses to inactivated vaccines in children with chronic hepatitis B (CHB) are still limited. Methods: In this prospective observational study, CHB children after primary inactivated SARS-CoV-2 vaccines were recruited consecutively and followed up for 1 year. CHB adults from another cohort study (NCT05007665) were used as a control. The receptor-binding domain IgG antibody (anti-RBD-IgG), neutralizing antibody (NAb), neutralization against Omicron (BA2.12.1, BA.4 and BA.5), and memory B -cell (MBC) responses were evaluated. Results: Overall, 115 CHB children and 351 CHB adults were included in this analysis. The antibody titers decreased over the first ~180 days and then plateaued up to 1 year in CHB children. However, lower and faster declines in antibody responses were observed in CHB adults. Interestingly, the seroprevalence of antibodies was still high after over 8 months in CHB children (anti-RBD-IgG [90%] and NAbs [83%]). However, neutralization against Omicron subvariants was significantly reduced in CHB children (-3.68-fold to -8.60-fold). Notably, neutralization against the BA.5 subvariant was obviously diminished in CHB children compared with adults. Moreover, CHB children had similar RBD-specific MBCs but higher RBD-specific atypical MBCs compared with adults. Conclusion: Inactivated vaccination could elicit more robust and durable antibody responses to the wild-type SARS-CoV-2 strain in CHB children than in CHB adults but showed inferior responses to Omicron subvariants (especially to the BA.5 strain). Hence, new Omicron-related or all-in-one vaccines are needed immediately for CHB children.

Epstein-Barr virus variation in people living with human immunodeficiency virus in southeastern China.

BACKGROUND: Patients infected with HIV are at high risk of developing Epstein-Barr Virus (EBV)-related diseases. The genotype and viral biological behavior of EBV infection in patients with human immunodeficiency virus-1 (HIV) in China remain unclear. This study analyzed the characteristics of EBV in patients infected with HIV in southeastern China. METHODS: A total of 162 HIV-infected patients and 52 patients without HIV were enrolled in this study. EBV viral load in blood was determined by fluorescence quantitative PCR. EBV typing was performed using saliva according to polymorphisms in the EBNA3C region. EBV LMP-1 carboxy terminus (C-ter) was sequenced, and compared with the epidemic strains in the world. RESULTS: Among HIV infected patients, the EBV strain variant was mainly EBV-1, while EBV-2 had a higher viral load than EBV-1 (P = 0.001) and EBV-1/2 (P = 0.002). HIV infected patients had higher active virus replication. The EBV LMP-1 variants were mainly the China1 variant. HIV-infected patients had different nucleic acid positions of 30-bp deletion (del30) and had a higher incidence of high 33-bp tandem repeats (rep33) copies than non-HIV-infected patients. There was a difference in the mutations of EBV LMP-1 C-ter del30 and ins15 between HIV infected patients and the control group (P < 0.001). CONCLUSION: In southeastern China, EBV in HIV-infected patients had higher active virus replication; EBV infection was mainly EBV-1, and EBV-2 infection has higher EBV virus load; hotspot mutations of LMP-1 C-ter were different between HIV-infected patients and non-HIV-infected patients. TRIAL REGISTRATION: This study was approved by the ethics committee of the First Affiliated Hospital of Zhejiang University School of Medicine (Approval No. 2018764), and registered in Chinese Clinical Trial Registry on 3 June 2019 (ChiCTR, ChiCTR1900023600, http://www.chictr.org.cn/usercenter.aspx ).

SENP2 knockdown in human adipocytes reduces glucose metabolism and lipid accumulation, while increases lipid oxidation.

Adipose tissue is one of the main regulative sites for energy metabolism. Excess lipid storage and expansion of white adipose tissue (WAT) is the primary contributor to obesity, a strong predisposing factor for development of insulin resistance. Sentrin-specific protease (SENP) 2 has been shown to play a role in metabolism in murine fat and skeletal muscle cells, and we have previously demonstrated its role in energy metabolism of human skeletal muscle cells. In the present work, we have investigated the impact of SENP2 on fatty acid and glucose metabolism in primary human fat cells by using cultured primary human adipocytes to knock down the SENP2 gene. Glucose uptake and oxidation, as well as accumulation and distribution of oleic acid into complex lipids were decreased, while oleic acid oxidation was increased in SENP2-knockdown cells compared to control adipocytes. Furthermore, lipogenesis was reduced by SENP2-knockdown in adipocytes. Although TAG accumulation relative to total uptake was unchanged, there was increased mRNA expression of metabolically relevant genes such as UCP1 and PPARGC1A and mRNA and proteomic data revealed increased levels of mRNA and proteins related to mitochondrial function by SENP2-knockdown. In conclusion, SENP2 is an important regulator of energy metabolism in primary human adipocytes and its knockdown reduce glucose metabolism and lipid accumulation, while increasing lipid oxidation in human adipocytes.

Efficacy and safety of lenalidomide in HIV-associated cryptococcal meningitis patients with persistent intracranial inflammation: an open-label, single-arm, prospective interventional study.

BACKGROUND: Patients with human immunodeficiency virus-associated cryptococcal meningitis (HIV-CM) have persistent intracranial inflammation despite negative cerebrospinal fluid (CSF) fungal cultures after optimal treatment for CM, which could be devastating for the central nervous system. However, a definitive treatment strategy for persistent intracranial inflammation despite optimal antifungal therapies is undefined. METHODS: We identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24-week, prospective, interventional study. All participants received lenalidomide (25 mg, p.o.) on days 1 to 21 of a 28-day cycle. Follow-up lasted for 24 weeks with visits at baseline and weeks 4, 8, 12, and 24. The primary endpoint was the change in clinical manifestations, routine CSF parameters, and MRI findings after lenalidomide treatment. An exploratory analysis was made on changes in cytokine levels in CSF. Safety and efficacy analyses were undertaken in patients who received at least one dose of lenalidomide. RESULTS: Of 14 participants, 11 patients completed the 24 weeks of follow-up. Rapid clinical remission following lenalidomide therapy was observed. Clinical manifestations (fever, headache, altered mentation) were reversed fully by week-4 and remained stable during follow-up. A significant reduction in white blood cell (WBC) count in CSF was noted occurred at week-4 (P = 0.009). The median protein concentration in CSF decreased from 1.4 (0.7-3.2) g/L at baseline to 0.9 (0.6-1.4) at week-4 (P = 0.004). The median albumin concentration in CSF decreased from 79.2 (48.4-149.8) mg/L at baseline to 55.3 (38.3-89.0) mg/L at week-4 (P = 0.011). The WBC count, protein level, and albumin level in CSF remained stable and approached a normal range through week-24. There was no significant change in immunoglobulin-G, intracranial pressure (ICP), or chloride-ion concentration at each visit. Brain MRI demonstrated multiple lesions to be absorbed post-therapy. Levels of tumor necrosis factor-α granulocyte colony stimulating factor, interleukin (IL)-6, and IL-17A decreased significantly during 24-week follow-up. Two (14.3%) patients had mild skin rash, which resolved spontaneously. Lenalidomide-related serious adverse events were not observed. CONCLUSION: Lenalidomide could improve persistent intracranial inflammation in HIV-CM patients significantly and was well tolerated without serious adverse events observed. And the additional randomized controlled study is required to further validate the finding.

Development and validation of a practical machine learning model to predict sepsis after liver transplantation.

BACKGROUND: Postoperative sepsis is one of the main causes of mortality after liver transplantation (LT). Our study aimed to develop and validate a predictive model for postoperative sepsis within 7 d in LT recipients using machine learning (ML) technology. METHODS: Data of 786 patients received LT from January 2015 to January 2020 was retrospectively extracted from the big data platform of Third Affiliated Hospital of Sun Yat-sen University. Seven ML models were developed to predict postoperative sepsis. The area under the receiver-operating curve (AUC), sensitivity, specificity, accuracy, and f1-score were evaluated as the model performances. The model with the best performance was validated in an independent dataset involving 118 adult LT cases from February 2020 to April 2021. The postoperative sepsis-associated outcomes were also explored in the study. RESULTS: After excluding 109 patients according to the exclusion criteria, 677 patients underwent LT were finally included in the analysis. Among them, 216 (31.9%) were diagnosed with sepsis after LT, which were related to more perioperative complications, increased postoperative hospital stay and mortality after LT (all p < .05). Our results revealed that a larger volume of red blood cell infusion, ascitic removal, blood loss and gastric drainage, less volume of crystalloid infusion and urine, longer anesthesia time, higher level of preoperative TBIL were the top 8 important variables contributing to the prediction of post-LT sepsis. The Random Forest Classifier (RF) model showed the best overall performance to predict sepsis after LT among the seven ML models developed in the study, with an AUC of 0.731, an accuracy of 71.6%, the sensitivity of 62.1%, and specificity of 76.1% in the internal validation set, and a comparable AUC of 0.755 in the external validation set. CONCLUSIONS: Our study enrolled eight pre- and intra-operative variables to develop an RF-based predictive model of post-LT sepsis to assist clinical decision-making procedure.

Postoperative sepsis is one of the main causes of mortality after liver transplantation (LT).Our results revealed that a larger volume of red blood cell infusion, ascitic removal, blood loss and gastric drainage, less volume of crystalloid infusion and urine, longer anesthesia time, higher level of preoperative TBIL were the top 8 important variables contributing to the prediction of post-LT sepsis.The Random Forest Classifier (RF) model showed the best overall performance to predict sepsis after LT in our study, which could assist in the clinical decision-making procedure.

FGF21 protects against hepatic lipotoxicity and macrophage activation to attenuate fibrogenesis in nonalcoholic steatohepatitis.

Analogues of the hepatokine fibroblast growth factor 21 (FGF21) are in clinical development for type 2 diabetes and nonalcoholic steatohepatitis (NASH) treatment. Although their glucose-lowering and insulin-sensitizing effects have been largely unraveled, the mechanisms by which they alleviate liver injury have only been scarcely addressed. Here, we aimed to unveil the mechanisms underlying the protective effects of FGF21 on NASH using APOE*3-Leiden.CETP mice, a well-established model for human-like metabolic diseases. Liver-specific FGF21 overexpression was achieved in mice, followed by administration of a high-fat high-cholesterol diet for 23 weeks. FGF21 prevented hepatic lipotoxicity, accompanied by activation of thermogenic tissues and attenuation of adipose tissue inflammation, improvement of hyperglycemia and hypertriglyceridemia, and upregulation of hepatic programs involved in fatty acid oxidation and cholesterol removal. Furthermore, FGF21 inhibited hepatic inflammation, as evidenced by reduced Kupffer cell (KC) activation, diminished monocyte infiltration, and lowered accumulation of monocyte-derived macrophages. Moreover, FGF21 decreased lipid- and scar-associated macrophages, which correlated with less hepatic fibrosis as demonstrated by reduced collagen accumulation. Collectively, hepatic FGF21 overexpression limits hepatic lipotoxicity, inflammation, and fibrogenesis. Mechanistically, FGF21 blocks hepatic lipid influx and accumulation through combined endocrine and autocrine signaling, respectively, which prevents KC activation and lowers the presence of lipid- and scar-associated macrophages to inhibit fibrogenesis.

High-calorie modern diets have contributed to growing rates of obesity-linked diseases. One such disease is non-alcoholic steatohepatitis or NASH for short, which affects about 5% of adults in the United States. The livers of people with this condition accumulate fat, become inflamed, and develop scar tissue. People with NASH are also at increased risk of developing liver cancer, type 2 diabetes, and heart disease. Currently, no drugs are available to treat the condition and prevent such severe complications. Previous research has shown the liver produces a stress hormone, called FGF21, in response to fat accumulation. This hormone boosts fat burning and so helps to reduce excess fat in the liver. Drugs that mimic FGF21 have already been developed for type 2 diabetes. But so far, it was unclear if such drugs could also help reduce liver inflammation and scarring in patients with NASH. Liu et al. show that increasing the production of FGF21 in mice with a NASH-like condition reduces fat accumulation, liver inflammation, and scarring. In the experiments, the researchers used gene therapy to ramp up FGF21 production in the livers of mice that develop obesity and a NASH-like condition when fed a high-fat diet for 23 weeks. Increasing FGF21 production prevented the mice from developing obesity while on the high fat diet by making the body burn more fat in the liver and brown fat tissue. The treatment also reduced inflammation and prevented scarring by reducing the number and activity of immune cells in the liver. Increasing the production of the stress hormone FGF21 prevents diet-induced obesity and NASH in mice fed a high-fat diet. More studies are necessary to determine if using gene therapy to increase FGF21 may also cause weight loss and could reverse liver damage in mice that already have NASH. If this approach is effective in mice, it may be tested in humans, a process that may take several years. If human studies are successful, FGF21-boosting therapy might provide a new treatment approach for obesity or NASH.

Elevated Adipocyte Membrane Phospholipid Saturation Does Not Compromise Insulin Signaling.

Increased saturated fatty acid (SFA) levels in membrane phospholipids have been implicated in the development of metabolic disease. Here, we tested the hypothesis that increased SFA content in cell membranes negatively impacts adipocyte insulin signaling. Preadipocyte cell models with elevated SFA levels in phospholipids were generated by disrupting the ADIPOR2 locus, which resulted in a striking twofold increase in SFA-containing phosphatidylcholines and phosphatidylethanolamines, which persisted in differentiated adipocytes. Similar changes in phospholipid composition were observed in white adipose tissues isolated from the ADIPOR2-knockout mice. The SFA levels in phospholipids could be further increased by treating ADIPOR2-deficient cells with palmitic acid and resulted in reduced membrane fluidity and endoplasmic reticulum stress in mouse and human preadipocytes. Strikingly, increased SFA levels in differentiated adipocyte phospholipids had no effect on adipocyte gene expression or insulin signaling in vitro. Similarly, increased adipocyte phospholipid saturation did not impair white adipose tissue function in vivo, even in mice fed a high-saturated fat diet at thermoneutrality. We conclude that increasing SFA levels in adipocyte phospholipids is well tolerated and does not affect adipocyte insulin signaling in vitro and in vivo.

Visible-Light-Induced Tandem Radical Brominative Addition/Cyclization of Activated Alkynes with CBr4 for the Synthesis of 3-Bromocoumarins.

A visible-light-induced tandem radical brominative addition/spiro-cyclization/1,2-ester migration of activated alkynes with CBr4 is developed. This protocol features good functional group tolerance, operational simplicity, and mild reaction conditions without the use of catalysts and external additives, providing easy access to valuable 3-bromocoumarins in generally high yields.

Tree-based, two-stage risk factor analysis for postoperative sepsis based on Sepsis-3 criteria in elderly patients: A retrospective cohort study.

Background: Sepsis remains the leading cause of postoperative death in elderly patients and is defined as organ dysfunction with proven or suspected infection according to Sepsis-3 criteria. To better avoid potential non-linear associations between the risk factors, we firstly used a tree-based analytic methods to explore the putative risk factors of geriatric sepsis based on the criteria in the study. Methods: Data of 7,302 surgical patients aged ≥ 65 years at the Third Affiliated Hospital of Sun Yat-sen University from January 2015 to September 2020 were collected. An analytic method that combined tree-based analysis with the method of Mantel-Haenszel and logistic regression was adopted to assess the association between 17 putative risk factors and postoperative sepsis defined by the Sepsis-3 guideline by controlling 16 potential confounding factors. Results: Among the 16 potential covariates, six major confounders were statistically identified by the tree-based model, including cerebrovascular diseases, preoperative infusion of red blood cells, pneumonia, age ≥ 75, malignant tumor and diabetes. Our analysis indicated that emergency surgery increases the risk of postoperative sepsis in elderly patients by more than six times. The type of surgery is also a crucial risk factor for sepsis, particularly transplantation and neurosurgery. Other risk factors were duration of surgery > 120 min, administration of steroids, hypoalbuminemia, elevated creatinine, blood urea nitrogen, hematocrit, platelets, glucose, white blood cell count, abnormal neutrophil-to-lymphocyte ratio and elevated hsCRP-to-albumin ratio. Conclusions: Our study uses an effective method to explore some risk factors for postoperative sepsis in elderly by adjusting many potential confounders and it can provide information for intervention design.

TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis.

The fatty acid composition of phosphatidylethanolamine (PE) determines cellular metabolism, oxidative stress, and inflammation. However, our understanding of how cells regulate PE composition is limited. Here, we identify a genetic locus on mouse chromosome 11, containing two poorly characterized genes Tlcd1 and Tlcd2, that strongly influences PE composition. We generated Tlcd1/2 double-knockout (DKO) mice and found that they have reduced levels of hepatic monounsaturated fatty acid (MUFA)-containing PE species. Mechanistically, TLCD1/2 proteins act cell intrinsically to promote the incorporation of MUFAs into PEs. Furthermore, TLCD1/2 interact with the mitochondria in an evolutionarily conserved manner and regulate mitochondrial PE composition. Lastly, we demonstrate the biological relevance of our findings in dietary models of metabolic disease, where Tlcd1/2 DKO mice display attenuated development of non-alcoholic steatohepatitis compared to controls. Overall, we identify TLCD1/2 proteins as key regulators of cellular PE composition, with our findings having broad implications in understanding and treating disease.

Outcome of Lenalidomide Treatment for Cognitive Impairment Caused by Immune Reconstitution Inflammatory Syndrome in Patients with HIV-Related Cryptococcal Meningitis.

Purpose: Cognitive impairment associated with human immunodeficiency virus (HIV)-related cryptococcal meningitis (HCM) in the context of immune reconstitution inflammatory syndrome is difficult to address. This study was a follow-up of lenalidomide treatment outcomes in patients with HCM and cognitive impairment after complete cryptococcal clearance. Patients and Methods: Seven HCM patients with neuroinflammation and cognitive impairment after complete cryptococcal clearance were enrolled in this prospective study. Neurocognitive assessment, clinical examination and cerebrospinal fluid (CSF) assays were performed before and after lenalidomide treatment. Results: After lenalidomide treatment, the Montreal Cognitive Assessment [week (W) 0 (median [interquartile range]: 23.0 (13.0-24.0) vs W24: 26.0 (24.0-28.00), P=0.018] and International HIV Dementia Scale scores [W0: 9.0 (2.5-10.5) vs W24: 11.0 (10.00-12.0), P=0.028] improved significantly, mainly in the domain of memory function. There was no significant difference in the Center for Epidemiological Research Depression scores for anxiety and depression before and after treatment. Further stratified analyses revealed that the patients with cognitive improvement group had higher levels of CSF white blood cells [94.0 (44.0-180.0) vs 0 (0-1.5), P=0.032], CSF protein [4.9 (3.0-6.6) vs 0.6 (0.5-0.7), P=0.034], CSF albumin [318.5 (190.9-346.5) vs 33.5 (30.4-46.2), P=0.034], and CSF IgG [160.5 (73.8-256. 0) vs 4.7 (4.3-7.4), P=0.034] but a lower CSF glucose level [2.4 (2.0-2.7) vs 2.8 (2.8-3.9), P=0.032] than the patients with cognitive non-improvement group before treatment. CSF inflammatory cytokines of the growth-related oncogene, interleukin [IL]-10, granulocyte-colony stimulating factor, IL-6, IL-8, complement factor H, tumor necrosis factor-α, and α-2 macroglobulin were obviously decreased in patients with cognitive improvement group after lenalidomide treatment. Conclusion: Lenalidomide potentially reduces cognitive impairment caused by immune reconstitution inflammatory syndrome in patients with HCM after cryptococcal clearance by inhibiting intracranial inflammation.

Lenalidomide potentially reduced the level of cell- associated HIV RNA and improved persistent inflammation in patients with HIV-associated cryptococcal meningitis a pilot study.

Background: The HIV-1 reservoir is a major barrier to curative strategies. Inflammation is an important factor for HIV-1 reservoir persistence. Lenalidomide regulates inflammatory cytokines efficiently. We examined whether lenalidomide could inhibit HIV-1 transcription and reduce systemic inflammation in people living with HIV. Methods: Lenalidomide was administered orally for 48 weeks to patients with HIV-associated cryptococcal meningitis (HIV-CM). A HIV-1 latency model was treated with or without lenalidomide ex vivo for 5 days. The primary endpoints were change in HIV reservoir markers and inflammatory cytokines in both the cohort and cell model. Results: Thirteen participants were enrolled from May 2019 to September 2020. The median change in cell-associated (CA) HIV RNA between baseline and 48 weeks was 0.81 log10 copies/million peripheral blood mononuclear cells (PBMCs). The CA HIV RNA decreased significantly in the cohort (P = 0.021). Serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) gradually diminished with lenalidomide treatment until 48 weeks (P = 0.007, P = 0.014, respectively). C-reactive protein/IL-6/TNF-α and CA HIV RNA were significantly correlated (P = 0.0027, 0.0496, and 0.0346, respectively). Lenalidomide also significantly decreased HIV core P24 (P = 0.0038) and CA HIV RNA in CD8-depleted PBMCs (P = 0.0178) ex vivo. TNF-α and IL-6 were significantly reduced in the CD8-depleted PBMC supernatant (P = 0.004, P < 0.0001, respectively) while IL-10 levels increased significantly on lenalidomide compared to no-lenalidomide treatment (P < 0.0001). Conclusions: Lenalidomide was preliminarily confirmed to reduce the level of cell- associated HIV RNA and improve persistent inflammation in patients with HIV-Associated cryptococcal meningitis, which was a potential intervention for clinical use to inhibit viral transcription of the HIV-1 reservoir and reduced HIV-related inflammation in HIV-1 patients during ART.

Differential In Vitro Effects of SGLT2 Inhibitors on Mitochondrial Oxidative Phosphorylation, Glucose Uptake and Cell Metabolism.

(1) The cardio-reno-metabolic benefits of the SGLT2 inhibitors canagliflozin (cana), dapagliflozin (dapa), ertugliflozin (ertu), and empagliflozin (empa) have been demonstrated, but it remains unclear whether they exert different off-target effects influencing clinical profiles. (2) We aimed to investigate the effects of SGLT2 inhibitors on mitochondrial function, cellular glucose-uptake (GU), and metabolic pathways in human-umbilical-vein endothelial cells (HUVECs). (3) At 100 µM (supra-pharmacological concentration), cana decreased ECAR by 45% and inhibited GU (IC5o: 14 µM). At 100 µM and 10 µM (pharmacological concentration), cana increased the ADP/ATP ratio, whereas dapa and ertu (3, 10 µM, about 10× the pharmacological concentration) showed no effect. Cana (100 µM) decreased the oxygen consumption rate (OCR) by 60%, while dapa decreased it by 7%, and ertu and empa (all 100 µM) had no significant effect. Cana (100 µM) inhibited GLUT1, but did not significantly affect GLUTs' expression levels. Cana (100 µM) treatment reduced glycolysis, elevated the amino acids supplying the tricarboxylic-acid cycle, and significantly increased purine/pyrimidine-pathway metabolites, in contrast to dapa (3 µM) and ertu (10 µM). (4) The results confirmed cana´s inhibition of mitochondrial activity and GU at supra-pharmacological and pharmacological concentrations, whereas the dapa, ertu, and empa did not show effects even at supra-pharmacological concentrations. At supra-pharmacological concentrations, cana (but not dapa or ertu) affected multiple cellular pathways and inhibited GLUT1.