Exploration of novel dihydroquinoxalinone derivatives as EGFRL858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer.

To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydroquinoxalinone (8-30) as the novel third-generation inhibitors against double mutant L858R/T790M in EGFR. Among them, compound 29 showed excellent kinase inhibitory activity against EGFRL858R/T790M with an IC50 value of 0.55 ± 0.02 nM and potent anti-proliferative activity against H1975 cells with an IC50 value of 5.88 ± 0.07 nM. Moreover, the strong down-regulation effect of EGFR-mediated signaling pathways and the promotion of apoptosis in H1975 cells confirmed its potent antitumor activities. Compound 29 was also demonstrated with good ADME profile in various in vitro assays. Further in vivo studies confirmed that compound 29 could suppress the growth of xenograft tumors. These results verified that compound 29 would be a promising lead compound for targeting drug-resistant EGFR mutations.

Trends in respiratory diseases before and after the COVID-19 pandemic in China from 2010 to 2021.

BACKGROUND: The ongoing benefits of coronavirus disease 2019 (COVID-19) nonpharmaceutical interventions (NPIs) for respiratory infectious diseases in China are still unclear. We aimed to explore the changes in seven respiratory infectious diseases before, during, and after COVID-19 in China from 2010 to 2021. METHODS: The monthly case numbers of seven respiratory infectious diseases were extracted to construct autoregressive integrated moving average (ARIMA) models. Eight indicators of NPIs were chosen from the COVID-19 Government Response Tracker system. The monthly case numbers of the respiratory diseases and the eight indicators were used to establish the Multivariable generalized linear model (GLM) to calculate the incidence rate ratios (IRRs). RESULTS: Compared with the year 2019, the percentage changes in 2020 and 2021 were all below 100% ranging from 3.81 to 84.71%. Pertussis and Scarlet fever started to increase in 2021 compared with 2020, with a percentage change of 183.46 and 171.49%. The ARIMA model showed a good fit, and the predicted data fitted well with the actual data from 2010 to 2019, but the predicted data was bigger than the actual number in 2020 and 2021. All eight indicators could negatively affect the incidence of respiratory diseases. The seven respiratory diseases were significantly reduced during the COVID-19 pandemic in 2020 and 2021 compared with 2019, with significant estimated IRRs ranging from 0.06 to 0.85. In the GLM using data for the year 2020 and 2021, the IRRs were not significant after adjusting for the eight indicators in multivariate analysis. CONCLUSION: Our study demonstrated the incidence of the seven respiratory diseases decreased rapidly during the COVID-19 pandemic in 2020 and 2021. At the end of 2021, we did see a rising trend for the seven respiratory diseases compared to the year 2020 when the NPIs relaxed in China, but the rising trend was not significant after adjusting for the NPIs indicators. Our study showed that NPIs have an effect on respiratory diseases, but Relaxation of NPIs might lead to the resurgence of respiratory diseases.

A long trend of sexually transmitted diseases before and after the COVID-19 pandemic in China (2010-21).

BACKGROUND: The longer ongoing benefits of coronavirus disease 2019 (COVID-19) non-pharmaceutical interventions (NPIs) for sexually transmitted diseases (STDs) in China are still unclear. We aimed to explore the changes in five STDs (AIDS, hepatitis B, hepatitis C, gonorrhoea, and syphilis) before, during, and after the COVID-19 pandemic in mainland China, from 2010 to 2021. METHODS: The number of the monthly reported cases of the five STDs were extracted from the website to construct the Joinpoint regression and autoregressive integrated moving average (ARIMA) models. Eight indicators reflecting NPIs were chosen from the COVID-19 Government Response Tracker system. The STDs and eight indicators were used to establish the Multivariable generalised linear model (GLM) to calculate the incidence rate ratios (IRRs). RESULTS: With the exception of hepatitis B, the other four STDs (AIDS, hepatitis C, gonorrhoea, and syphilis) had a positive average annual percent change over the past 12years. All the ARIMA models had passed the Ljung-Box test, and the predicted data fit well with the data from 2010 to 2019. All five STDs were significantly reduced in 2020 compared with 2019, with significant estimated IRRs ranging from 0.88 to 0.92. In the GLM, using data for the years 2020 (February-December) and 2021, the IRRs were not significant after adjusting for the eight indicators in multivariate analysis. CONCLUSION: Our study demonstrated that the incidence of the five STDs decreased rapidly during the COVID-19 pandemic in 2020. A recovery of STDs in 2021 was found to occur compared with that in 2020, but the rising trend disappeared after adjusting for the NPIs. Our study demonstrated that NPIs have an effect on STDs, but the relaxation of NPI usage might lead to a resurgence.

pH-Responsive and liver-targeting drug delivery system for combination delivery of artesunate with arsenic trioxide prodrug against hepatocellular carcinoma.

OBJECTIVE: Arsenic trioxide (ATO) exerts therapeutic effects on various solid tumors, and artesunate (ART) synergizes with antitumor drugs. We herein combined ART and an ATO prodrug (ATOP) in pH-responsive and liver-targeting liposomes to improve targeted hepatocellular carcinoma (HCC) treatment. METHODS: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-hydrazone (HYD)-polyethylene glycol (PEG)-glycyrrhetinic acid (GA) (DSPE-HYD-PEG-GA) was synthesized and characterized. The optimal ratio of ART and ATOP was selected. Calcium arsenate nanoparticles (CaAs NPs) and DSPE-HYD-PEG-GA@ART/CaAs NPs liposomes were prepared and their physicochemical properties were characterized. Their intracellular uptake, intracellular localization, uptake pathway identification, cytotoxicity, proapoptotic effects, and relevant mechanisms were studied. RESULTS: The DSPE-HYD-PEG-GA was successfully synthesized. The best ratio of ART and ATOP was 7:1. The particle size of CaAs NPs under transmission electron microscopy was 142.39 ± 21.50 nm. Arsenic (As), calcium, and oxygen elements were uniformly distributed in CaAs NPs, and the drug loading and encapsulation efficiency of As are 37.28% and 51.40%, respectively. The liposomes were elliptical, and the particle size was 100.91 ± 39.31 nm. The liposome cell intake was significantly increased in Huh-7 cells. The liposomes entered the cell through macropinocytosis and caveolin-mediated endocytosis and were predominantly distributed in the cytoplasm. They exerted an excellent inhibitory effect on Huh-7 cells and promoted tumor cell apoptosis through lipid peroxidation, mitochondrial membrane potential reduction, and cell-cycle blockage. CONCLUSIONS: The pH-responsive and liver-targeting drug delivery system for the combination delivery of ART with ATOP showed promising effects on hepatocellular carcinoma (HCC).

[Clinical features of 19 children infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 in Hangzhou, China]. / 杭州市19ä¾‹æ–°åž‹å† çŠ¶ç— æ¯’Omicronå˜å¼‚æ ªæ„ŸæŸ“å„¿ç«¥çš„ä¸´åºŠç‰¹å¾.

OBJECTIVES: To study the clinical features of children infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: The medical data of 19 children who were diagnosed with SARS-CoV-2 Omicron variant infection from January 28 to March 3, 2022 in Hangzhou were retrospectively reviewed. RESULTS: Among the 19 children, there were 7 boys (37%) and 12 girls (63%), and their age ranged from 6 months to 16 years, with a median age of 2 years and 1 month. Most of these children were infants and young children (aged ≤3 years, accounting for 53%). Among these children, 11 (58%) were unvaccinated with SARS-CoV-2 vaccine and 8 (42%) were vaccinated with SARS-CoV-2 vaccine, and 3 children (16%) had a history of underlying diseases. All 19 children had a clear history of close contact with persons infected with SARS-CoV-2, and 10 children (53%) were involved in the cluster outbreak in a maternal and infant care center. In terms of clinical classification, 13 children (68%) had mild coronavirus disease 2019 (COVID-19) and 6 (32%) had common COVID-19, with no severe cases of COVID-19. The most common clinical symptoms were cough (100%) and fever (63%). The children with a normal peripheral white blood cell count accounted for 84%, and those with a normal lymphocyte count accounted for 68%. There were no significant abnormalities in platelet count, procalcitonin, liver function parameters (alanine aminotransferase and aspartate aminotransferase), and renal function parameters (creatinine and urea). Six children (32%) had obvious signs of pneumonia on chest CT. All 19 children were given symptomatic treatment, and 12 children (63%) were given aerosol inhalation of interferon α. All children were cured and discharged. CONCLUSIONS: Children infected with Omicron variant strains are more common in infants and young children, with mild symptoms and good prognosis. Most of the children have a history of close contact with persons infected with SARS-CoV-2, and epidemic prevention and control should be strengthened in places with many infants and children, such as maternal and infant care centers.

The Chinese Society of Hepatology position statement on the redefinition of fatty liver disease.

Fatty liver disease associated with metabolic dysfunction is of increasing concern in mainland China, the world's most populous country. The incidence of fatty liver disease is highest in China, surpassing the incidence in European countries and the USA. An international consensus panel recently published an influential report recommending a novel definition of fatty liver disease associated with metabolic dysfunction. This recommendation includes a switch in name from non-alcoholic fatty liver disease (NAFLD) to metabolic (dysfunction)-associated fatty liver disease (MAFLD) and adoption of a set of positive criteria for disease diagnosis that are independent of alcohol intake or other liver diseases. Given the unique importance of this proposal, the Chinese Society of Hepatology (CSH) invited leading hepatologists and gastroenterologists representing their respective provinces and cities to reach consensus on alternative definitions for fatty liver disease from a national perspective. The CSH endorses the proposed change from NAFLD to MAFLD (supported by 95.45% of participants). We expect that the new definition will result in substantial improvements in health care for patients and advance disease awareness, public health policy, and political, scientific and funding outcomes for MAFLD in China.

Severity-associated markers and assessment model for predicting the severity of COVID-19: a retrospective study in Hangzhou, China.

BACKGROUND: The severity of COVID-19 associates with the clinical decision making and the prognosis of COVID-19 patients, therefore, early identification of patients who are likely to develop severe or critical COVID-19 is critical in clinical practice. The aim of this study was to screen severity-associated markers and construct an assessment model for predicting the severity of COVID-19. METHODS: 172 confirmed COVID-19 patients were enrolled from two designated hospitals in Hangzhou, China. Ordinal logistic regression was used to screen severity-associated markers. Least Absolute Shrinkage and Selection Operator (LASSO) regression was performed for further feature selection. Assessment models were constructed using logistic regression, ridge regression, support vector machine and random forest. The area under the receiver operator characteristic curve (AUROC) was used to evaluate the performance of different models. Internal validation was performed by using bootstrap with 500 re-sampling in the training set, and external validation was performed in the validation set for the four models, respectively. RESULTS: Age, comorbidity, fever, and 18 laboratory markers were associated with the severity of COVID-19 (all P values < 0.05). By LASSO regression, eight markers were included for the assessment model construction. The ridge regression model had the best performance with AUROCs of 0.930 (95% CI, 0.914-0.943) and 0.827 (95% CI, 0.716-0.921) in the internal and external validations, respectively. A risk score, established based on the ridge regression model, had good discrimination in all patients with an AUROC of 0.897 (95% CI 0.845-0.940), and a well-fitted calibration curve. Using the optimal cutoff value of 71, the sensitivity and specificity were 87.1% and 78.1%, respectively. A web-based assessment system was developed based on the risk score. CONCLUSIONS: Eight clinical markers of lactate dehydrogenase, C-reactive protein, albumin, comorbidity, electrolyte disturbance, coagulation function, eosinophil and lymphocyte counts were associated with the severity of COVID-19. An assessment model constructed with these eight markers would help the clinician to evaluate the likelihood of developing severity of COVID-19 at admission and early take measures on clinical treatment.

Preparation, evaluation, and in vitro cytotoxicity studies of artesunate-loaded glycyrrhetinic acid decorated PEG-PLGA nanoparticles.

OBJECTIVE: The objective of this study was to prepare the liver targeting drug delivery system (TDDS) of artesunate (ART)-loaded polyethylene glycol (PEG)-poly(d,l-lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) modified by glycyrrhetinic acid (GA), and evaluate its in vitro cytotoxicity. SIGNIFICANCE: The GA-PEG-PLGA-ART NPs enhanced the in vitro cytotoxicity on HCC cell lines. The development of GA-PEG-PLGA NPs will greatly push the clinical applications of ART as a novel anticancer drug. METHODS: The NPs were prepared using solvent evaporation method, and the formulation was optimized through an orthogonal design. In addition, physical properties were determined, including particle size, polydispersity index (PDI), zeta potential (ZP), morphology, drug loading capacity (LC) and encapsulation efficiency (EE), and in vitro drug release. Moreover, the in vitro cytotoxicity of NPs with three human cancer cell lines viz. HepG2, Hep3B, and SMCC-7721 was conducted using the SRB assay. Additionally, lyophilization was conducted to improve the long-term physical stability. RESULTS: The GA-PEG-PLGA-ART NPs have spherical shape, small particle size (around 88 nm) with a narrow size distribution (PDI < 0.3), high drug LC (up to 59.3 ± 1.65%), and high EE (up to 73.13 ± 5.17%). In vitro drug release behavior showed that drugs were released from NPs in a sustained and controlled release pattern. Cytotoxicity study indicated the NPs achieved lower cancer cell survival fraction. The GA-PEG-PLGA NPs freeze-dried with 3% (w/v) of mannitol showed better effect on long-term physical stability. CONCLUSION: The GA-PEG-PLGA-ART NPs appear as a potential liver targeted intracellular delivery platform for ART.

Protective effect of apigenin magnesium complex on H2O2-induced oxidative stress and inflammatory responses in rat hepatic stellate cells.

Context: Apigenin displays antioxidant and anti-inflammatory effects. However, effects of apigenin magnesium (AM) complex on these aspects remain unknown.Objective: This study investigated the effects of AM complex on oxidative stress and inflammatory responses in hydrogen peroxide (H2O2)-induced rat hepatic stellate cells (HSCs).Materials and methods: The antioxidant and anti-inflammatory effects of AM complex at concentrations of 0.625, 1.25, and 2.5 mg/mL were evaluated, comparing to HSCs treated by H2O2 alone. Cell viability, reactive oxygen species (ROS), the activity of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO), interleukin 6 (IL-6), and nuclear factor-kappa B (NF-κB) levels were measured. Moreover, cell apoptosis, mRNA expression levels of transforming growth factor-ß (TGF-ß), NF-κB, and inducible nitric oxide synthase (iNOS) were assessed.Results: AM complex significantly inhibited oxidative stress and inflammatory response at concentrations of 0.625, 1.25, and 2.5 mg/mL (IC50 = 1.679 mg/mL). AM complex elevated the survival rate of H2O2-treated HSCs and had no toxic effects on HSCs. AM complex also promoted SOD activity and GSH levels but suppressed ROS, MDA, and NO levels. Additionally, AM complex decreased IL-6 and NF-κB levels, gene expression of TGF-ß, NF-κB, and iNOS, as well as induced apoptosis of HSCs.Discussion and conclusions: Data indicated that AM complex mitigated oxidative stress and inflammatory responses on H2O2-treated HSCs, suggesting that AM complex is a possible candidate for anti-hepatic diseases. Additional efforts, both in vivo and in humans, are required to assess of AM complex as a potential therapeutic drug in liver diseases.

Design, synthesis, and biological evaluation of novel 3-(thiophen-2-ylthio)pyridine derivatives as potential multitarget anticancer agents.

A series of novel 3-(thiophen-2-ylthio)pyridine derivatives as insulin-like growth factor 1 receptor (IGF-1R) inhibitors was designed and synthesized. IGF-1R kinase inhibitory activities and cytotoxicities against HepG2 and WSU-DLCL2 cell lines were tested. For all of these compounds, potent cancer cell proliferation inhibitory activities were observed, but not through the inhibition of IGR-1R. Selected compounds were further screened against various kinases. Typical compound 22 (50% inhibitory concentration [IC50 ] values, HepG2: 2.98 ± 1.11 µM and WSU-DLCL2: 4.34 ± 0.84 µM) exhibited good inhibitory activities against fibroblast growth factor receptor-2 (FGFR2), FGFR3, epidermal growth factor receptor, Janus kinase, and RON (receptor originated from Nantes), with IC50 values ranging from 2.14 to 12.20 µM. Additionally, the cell-cycle analysis showed that compound 22 could arrest HepG2 cells in the G1/G0 phase. Taken together, all the experiments confirmed that the compounds in this series were multitarget anticancer agents worth further optimizing.

Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.

In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.

Association of arginine vasopressin receptor 1a gene polymorphisms with hepatorenal syndrome.

OBJECTIVE: To assess the association of arginine vasopressin receptor 1a gene single nucleotide polymorphisms with type I hepatorenal syndrome. METHODS: The case-control study was conducted at the Hangzhou City Xixi Hospital, Hangzhou, China, from January 2012 to June 2014, and comprised patients with type I hepatorenal syndrome and individuals with cirrhosis who acted as the control group. Arginine vasopressin receptor 1a gene rs113481894 locus single nucleotide polymorphisms were analysed by high-resolution melting methods. Statistical analysis was performed using SPSS 17. RESULTS: Of the 60 participants, 28(46.7%) were in the hepatorenal syndrome group and 32(53.3%) were controls. The mean age was 42.21±11.30years in the hepatorenal syndrome group and 43.69±12.60in the control group (p=0.64). Mean total bilirubin, albumin and prothrombin activity levels were 154.76±51.58, 49.30±24.67 and 33.42±3.69 in the hepatorenal syndrome group compared to 181.26±64.46, 41.78±17.52 and32.98±4.81among controls (p=0.09, p=0.18 and p=0.70). Statistically significant differences were found in the distributions of arginine vasopressin receptor 1a gene rs113481894 locus T allele between type I hepatorenal syndrome patients and the control group (odds ratio= 2.230; p= 0.040). CONCLUSIONS: T allele located at arginine vasopressin receptor 1a receptor promoter rs113481894 locus may be associated with the pathogenesis of type I hepatorenal syndrome.

Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors.

A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC50 less than 20nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC50: 1.4±0.1nM) and cytotoxicities with IC50 values at 13.9±1.8nM and 9.5±0.5nM against RPMI 8226 and MM-1S, respectively. Additionally, the ex vivo blood cell proteasome inhibitory activities of compounds 24 and 27-29 demonstrated that the enzymatic metabolism in the whole blood could be well tolerated. All these experiments confirmed that the piperidine-containing non-covalent proteasome inhibitors are potential leads for exploring new anti-cancer drugs.

Acinetobacter baumannii: an evolving and cunning opponent.

Acinetobacter baumannii is one of the most common multidrug-resistant pathogens causing nosocomial infections. The prevalence of multidrug-resistant A. baumannii infections is increasing because of several factors, including unregulated antibiotic use. A. baumannii drug resistance rate is high; in particular, its resistance rates for tigecycline and polymyxin-the drugs of last resort for extensively drug-resistant A. baumannii-has been increasing annually. Patients with a severe infection of extensively antibiotic-resistant A. baumannii demonstrate a high mortality rate along with a poor prognosis, which makes treating them challenging. Through carbapenem enzyme production and other relevant mechanisms, A. baumannii has rapidly acquired a strong resistance to carbapenem antibiotics-once considered a class of strong antibacterials for A. baumannii infection treatment. Therefore, understanding the resistance mechanism of A. baumannii is particularly crucial. This review summarizes mechanisms underlying common antimicrobial resistance in A. baumannii, particularly those underlying tigecycline and polymyxin resistance. This review will serve as a reference for reasonable antibiotic use at clinics, as well as new antibiotic development.

Small molecules as modulators of the proteostasis machinery: Implication in cardiovascular diseases.

With the escalating prevalence of cardiovascular diseases, the substantial socioeconomic burden on healthcare systems is intensifying. Accumulating empirical evidence underscores the pivotal role of the proteostasis network in regulating cardiac homeostasis and function. Disruptions in proteostasis may contribute to the loss of protein function or the acquisition of toxic functions, which are intricately linked to the development of cardiovascular ailments such as atrial fibrillation, heart failure, atherosclerosis, and cardiac aging. It is widely acknowledged that the proteostasis network encompasses molecular chaperones, autophagy, and the ubiquitin proteasome system (UPS). Consequently, the proteostasis network emerges as an appealing target for therapeutic interventions in cardiovascular diseases. Numerous small molecules, acting as modulators of the proteostasis machinery, have exhibited therapeutic efficacy in managing cardiovascular diseases. This review centers on elucidating the role of the proteostasis network in various cardiovascular diseases and explores the potential of small molecules as therapeutic agents.

Prognostic value of the neutrophil-to-lymphocyte ratio and C-reactive-protein-to-prealbumin ratio in hospitalized older patients with coronavirus disease 2019.

The neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein-to-prealbumin ratio (CPAR) are novel markers of inflammation. The CPAR is an indicator of inflammation and malnutrition. We evaluated NLR and CPAR in combination as indicators of disease severity and prognosis in hospitalized older patients with coronavirus disease 2019 (COVID-19). A total of 222 hospitalized patients with COVID-19 (aged > 60 years) were divided into non-severe and severe groups. The severe group was subdivided into the surviving and deceased subgroups. We retrospectively assessed the predictive power of NLR and CPAR in combination (NLR + CPAR) to determine the prognosis of hospitalized older patients with COVID-19. The NLR and CPAR were significantly higher in the severe group than in the non-severe group (P < .001). Furthermore, the NLR and CPAR were higher in the deceased subgroup than in the surviving subgroup (P < .001). Pearson correlation analysis showed a highly significant positive correlation between NLR and CPAR (P < .001, r = 0.530). NLR + CPAR showed an area under the curve of 0.827 and sensitivity of 83.9% in the severe group; the area under the curve was larger (0.925) and sensitivity was higher (87.1%) in the deceased subgroup. The receiver operating characteristic curve of NLR + CPAR was significantly different from the receiver operating characteristic curves of either biomarker alone (P < .001). Kaplan-Meier analysis showed that patients in the severe group with elevated NLR + CPAR had a significantly lower 90-day survival rate than patients who lacked this finding (odds ratio 7.87, P < .001). NLR + CPAR may enable early diagnosis and assessment of disease severity in hospitalized older patients with COVID-19. This may also enable the identification of high-risk older patients with COVID-19 at the time of admission.

Development and Evaluation of a Nomogram for Predicting the Outcome of Immune Reconstitution Among HIV/AIDS Patients Receiving Antiretroviral Therapy in China.

This study aims to develop and evaluate a model to predict the immune reconstitution among HIV/AIDS patients after antiretroviral therapy (ART). A total of 502 HIV/AIDS patients are randomized to the training cohort and evaluation cohort. Least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression analysis are performed to identify the indicators and establish the nomogram for predicting the immune reconstitution. Decision curve analysis (DCA) and clinical impact curve (CIC) are used to evaluate the clinical effectiveness of the nomogram. Predictive factors included white blood cells (WBC), baseline CD4+ T-cell counts (baseline CD4), ratio of effector regulatory T cells to resting regulatory T cells (eTreg/rTreg) and low-density lipoprotein cholesterol (LDL-C) and are incorporated into the nomogram. The area under the curve (AUC) is 0.812 (95% CI, 0.767∼0.851) and 0.794 (95%CI, 0.719∼0.857) in the training cohort and evaluation cohort, respectively. The calibration curve shows a high consistency between the predicted and actual observations. Moreover, DCA and CIC indicate that the nomogram has a superior net benefit in predicting poor immune reconstitution. A simple-to-use nomogram containing four routinely collected variables is developed and internally evaluated and can be used to predict the poor immune reconstitution in HIV/AIDS patients after ART.

Early-stage neutralizing antibody level associated with the re-positive risk of Omicron SARS-CoV-2 RNA in patients recovered from COVID-19.

Post-discharge re-positivity of Omicron SARS-CoV-2 is challenging for the sufficient control of this pandemic. However, there are few studies about the risk of re-positivity. We aimed to explore the association of neutralizing antibodies (nAbs, AU/mL) with the incidence of re-positivity among patients recovered from COVID-19. A retrospective cohort study selected 318 Omicron-infected patients was conducted in China between December 2021 and April 2022. The peak value of nAb levels (nAb-peak) within 14 days of disease onset was defined as the baseline and was mainly used for the subsequent analyses. In the unadjusted, minimally adjusted, fully adjusted, and additionally adjusted for IgG models, a per-standard deviation (SD) increase in the nAb-peak values was significantly associated with a 59 %, 59 %, 50 %, and 75 % decreased risk of Omicron SARS-CoV-2 re-positivity during post-discharge surveillance, respectively. Stratified analyses showed no significant changes in the relationship between nAbs and re-positivity. Our study suggested that the increase in baseline nAb levels independently associated with a low risk of re-positivity in patients recovered from COVID-19.

Dynamics of CD4+ T-Cells and Neutralizing Antibody Responses to Three Consecutive Doses of Inactivated COVID-19 Vaccines in PLWH.

Background: Comprehensive characterization of safety and immune responses to vaccines is crucial for the prevention and treatment of COVID-19 among people living with HIV (PLWH). This study aimed to investigate the dynamic changes in SARS-CoV-2-specific CD4+ T-cell subsets and neutralizing antibody after three consecutive doses of inactivated COVID-19 vaccines (BBIBP-CorV) among PLWH. Methods: The blood samples were collected from 165 PLWH, including 66 PLWH in the 3-month interval between the second and third dose (cohort 1) and 99 PLWH in the 5-month interval (cohort 2). Blood collection for immunogenicity analysis was performed at 1-month post-2nd vaccination, pre-3rd vaccination, and within 2-month post-3rd vaccination. Wilcoxon matched-pairs signed-rank test was applied to compare the SARS-CoV-2-specific CD4+ T cell subsets and neutralizing antibody level at different time points. The relationship among CD4+ T-cells, Tregs subpopulations and SARS-CoV-2-specific neutralizing antibody level were evaluated with Spearman non-parametric correlation test. Results: No serious adverse reactions were found among PLWH. After two-dose or three-dose inactivated COVID-19 vaccination, the absolute counts of CD4+ T-cells and Tregs subpopulations (CD4+CD25HighCD127Low Tregs, CD45RA+ rTregs and CD45RO+ eTregs) increased in two cohorts. Satisfactory SARS-CoV-2-specific neutralizing antibody responses to the third-dose vaccination were found in two cohorts, including significantly enhanced neutralizing antibody level and high neutralizing antibody seroconversion rate. In addition, SARS-CoV-2-specific neutralizing antibody level were positively associated with the absolute counts of CD4+ T-cells and Tregs subpopulations as well as the frequency of CD45RO+ eTregs in PLWH after three doses of vaccinations. Conclusion: The three doses of inactivated COVID-19 vaccination were both safe and effective to increase SARS-CoV-2-specific CD4+ T-cells and neutralizing antibody in two PLWH cohorts with different inoculation intervals.

Extending the dosing interval of COVID-19 vaccination leads to higher rates of seroconversion in people living with HIV.

Introduction: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is an effective way of protecting individuals from severe coronavirus disease 2019 (COVID-19). However, immune responses to vaccination vary considerably. This study dynamically assessed the neutralizing antibody (NAb) responses to the third dose of the inactivated COVID-19 vaccine administered to people living with human immunodeficiency virus (HIV; PLWH) with different inoculation intervals. Methods: A total of 171 participants were recruited: 63 PLWH were placed in cohort 1 (with 3-month interval between the second and third doses), while 95 PLWH were placed in cohort 2 (with 5-month interval between the second and third doses); 13 individuals were enrolled as healthy controls (HCs). And risk factors associated with seroconversion failure after vaccination were identified via Cox regression analysis. Results: At 6 months after the third vaccination, PLWH in cohort 2 had higher NAb levels (GMC: 64.59 vs 21.99, P < 0.0001) and seroconversion rate (68.42% vs 19.05%, P < 0.0001). A weaker neutralizing activity against the SARSCoV-2 Delta variant was observed (GMT: 3.38 and 3.63, P < 0.01) relative to the wildtype strain (GMT: 13.68 and 14.83) in both cohorts. None of the participants (including HCs or PLWH) could mount a NAb response against Omicron BA.5.2. In the risk model, independent risk factors for NAb seroconversion failure were the vaccination interval (hazed ration [HR]: 0.316, P < 0.001) and lymphocyte counts (HR: 0.409, P < 0.001). Additionally, PLWH who exhibited NAb seroconversion after vaccination had fewer initial COVID-19 symptoms when infected with Omicron. Discussion: This study demonstrated that the third vaccination elicited better NAb responses in PLWH, when a longer interval was used between vaccinations. Since post-vaccination seroconversion reduced the number of symptoms induced by Omicron, efforts to protect PLWH with risk factors for NAb seroconversion failure may be needed during future Omicron surges. Clinical trial registration: https://beta.clinicaltrials.gov/study/NCT05075070, identifier NCT05075070.