Analysis and Regulatory Mechanisms of Platelet-Related Genes in Patients with Ischemic Stroke.

It was found that ischemic stroke (IS) was associated with abnormal platelet activity and thrombosis. However, the potential significance of platelet-related genes (PRGs) in IS still needs to be more thorough. This study extracted IS-related transcriptome datasets from the Gene Expression Omnibus (GEO) database. The target genes were obtained by intersecting the differentially expressed genes (DEGs), the module genes related to IS, and PRGs, where the key genes of IS were screened by two machine learning algorithms. The key genes-based diagnostic model was constructed. Gene set enrichment analysis (GSEA) and the immune microenvironment analyses were analyzed targeting key genes in IS. The co-expression, TF-mRNA, and competitive endogenous RNAs (ceRNA) regulatory networks were constructed to reveal the potential regulation of key genes. Potential drugs targeting key genes were predicted as well. Totals of eight target genes were obtained and were associated with immune-related functions. Four platelet-related key genes were acquired, which were related to immunity and energy metabolism. The abnormal expressions of DOCK8, GIMAP5, ICOS were determined by the quantitative real-time polymerase chain reaction (qRT-PCR), and the significant correlations among these key genes were identified. Notably, hsa-miR-17-3p, hsa-miR-3158-3p, hsa-miR-423-3p, and hsa-miR-193a-8p could regulate all key genes at the same time. In addition, Caffeine, Carboplatin, and Vopratelimab were the targeted drugs of these key genes. This study identified four platelet-related key genes of IS, which might help to deepen the understanding of the role of platelet-related genes in the molecular mechanism of IS.

Elevated circulating PCSK9 level is associated with 28-day mortality in patients with sepsis: a prospective cohort study.

OBJECTIVES: Pro-protein convertase subtilisin/kexin 9 (PCSK9) decreases the clearance of the pathogenic lipids, supporting the potential role of PCSK9 in the prognosis of sepsis. METHODS: In this prospective cohort study, patients with sepsis were consecutively recruited from 1 to 2020 to 30 September 2021 at the First People's Hospital of Huaihua, China. All the eligible patients were categorized into low-PCSK9 and high-PCSK9 groups, based on their PCSK9 levels at admission. Time-dependent receiver operating characteristic curves and Cox proportional hazards regression were used to evaluate the association between PCSK9 level and 28-day mortality of sepsis. RESULTS: Of the 203 enrolled patients, 56 (27.59%) died during the 28-day follow-up. The PCSK9 level was positively related to the C-reactive protein level. The cut-off point of PCSK9 levels for 28-day mortality risk was 370 ng/ml. Through comparison between high-PCSK9 (> 370 ng/ml) with low-PCSK9 (≤ 370 ng/ml) groups, the adjusted HR for mortality was 2.56 (95% CI: 1.25-5.23, p = 0.01). CONCLUSIONS: The 28-day mortality of sepsis increased significantly as the baseline circulating PCSK9 level exceeded 370 ng/ml, indicating circulating PCSK9 levels may be a potential biomarker to predict the prognosis of sepsis.

Circulating prekallikrein levels are correlated with lipid levels in the chinese population: a cross-sectional study.

BACKGROUND: Recent evidence has revealed that circulating coagulation factor prekallikrein (PK), an important part of the kallikrein-kinin system, regulates cholesterol metabolism, but the association between serum PK and lipid levels is unclear. METHODS: This cross-sectional study included 256 subjects (aged from 1 month to 90 years) who underwent physical examinations at the First People's Hospital of Huaihua, China. After overnight fasting, serum was collected for PK and lipid testing. Spearman correlation analysis and multivariable logistic regression analysis were used to analyze the association of PK level with lipid levels and the likelihood risk of hyperlipidemia. The possible threshold value of PK was calculated according to the receiver operating characteristic (ROC) curve. RESULTS: The median serum PK level was 280.9 µg/mL (IQR 168.0, 377.0), and this level changed with age but not sex. The serum PK level was positively correlated with the serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. A nonlinear relationship was observed between serum PK and high-density lipoprotein cholesterol (HDL-C) levels. The serum PK level was positively correlated with HDL-C when its level was lower than 240 µg/mL and negatively correlated with HDL-C when its level was higher than 240 µg/mL. The regression analysis demonstrated that an elevated serum PK level was significantly associated with the likelihood risk of hypercholesterolemia and hypertriglyceridemia. The ROC curve showed that the possible threshold values of serum PK for hypercholesterolemia and hypertriglyceridemia occurrences were 344.9 µg/mL and 305.7 µg/mL, respectively. CONCLUSIONS: Elevated serum PK levels were significantly associated with the likelihood of hypercholesterolemia and hypertriglyceridemia, and the possible threshold values of PK levels were 344.9 µg/mL and 305.70 µg/mL, respectively, suggesting that higher PK levels may be a risk factor for cardiovascular diseases.

Protective Effect of GSK-3ß/Nrf2 Mediated by Dimethyl Fumarate in Middle Cerebral Artery Embolization Reperfusion Rat Model.

AIM: This study investigated the protective effect of dimethyl fumarate (DMF) in rats by mediating glycogen synthase kinase 3ß (GSK-3ß)/Nrf2 using the middle cerebral artery embolization reperfusion (MCAO/R) rat model. BACKGROUND: After an acute ischemic stroke (AIS), oxidative stress occurs. Dimethyl fumarate (DMF), a nuclear factor-E2-related factor 2 (Nrf2) activator, approved by the US Food and Drug Administration (FDA), was observed to regulate the Nrf2 pathway by acting as an anti-oxidative stress agent; however, whether this agent is involved in inhibiting GSK-3ß remains to be established. METHODS: DMF model was used to explore the effects of GSK-3ß on Nrf2 expression level, Nrf2- ARE binding activity and Nrf2/ARE downstream expression level of anti-oxidant stress protein in Cerebral ischemia-reperfusion injury (CIRI). 60 rats were randomly divided into Sham group, MCAO/R group, solvent control group (DMSO group) and DMF treatment group, with 15 rats in each group. The MCAO/R, DMSO and DMF groups were considered in the MCAO/R model using the modified thread embolization method. In contrast, the Sham group was only anaesthetized and disinfected, and tissue muscle was dissected without inserting suture emboli. DMF group was gavaged with 45mg/kg per day of DMF, DMSO control group was gavaged with DMSO of equal volume, while MCAO/R group was only modeled without any intragastric treatment. The rats were treated seven days after the operation, and a neurological function Longa score was estimated. The rats were sacrificed seven days later, and the infarct volume was assessed by TTC staining. Hematoxylin- eosin (HE) staining was used to observe the pathological changes in rat brain tissue. Nissl staining was used to observe the expression of neurons in the infarcted cortex. Western blotting (WB) was used to observe the protein expression levels of GSK-3ß, Nrf2, downstream heme oxygenase 1 (HO1) and NADPH quinone oxidoreductase 1 (NQO1) in four groups. The expression levels of GSK-3ß and Nrf2 in the four groups were observed by immunohistochemistry and immunofluorescence. RESULTS: (1) The Longa score of the MCAO/R, DMSO and DMF groups was found to be higher compared to the Sham group, indicating successful operation. The Longa score of the DMF group was lower than that of the other three groups 4-7 days after surgery (P<0.05). (2) HE and Nissl staining showed that the DMF group had lower neuron necrosis and higher gliosis compared to the control groups. (3) TTC staining results showed that the infarct volume of the DMF group was significantly smaller than the MCAO/R and DMSO groups. (4) Protein results showed that the GSK-3ß expression in the DMF group was lower than that in all groups, while the expression of Nrf2, HO1 and NQO1 was higher compared to other groups. CONCLUSION: DMF can reduce neurological deficits and infarct size in the MCAO/R model. The protective effect may be related to decreased GSK-3ß expression and increased Nrf2 expression, which may play a role in anti-oxidative stress.

Efficacy and Safety of Triple versus Dolutegravir-based Dual Therapy in Patients with HIV-1 Infection: A Meta-analysis of Randomized Controlled Trials.

A new strategy of simplification therapy shown the unique benefits in clinical treatment, by reducing pill burden and avoid drug exposure. To provide more evidence for the strategy, we compared the efficacy and safety of dolutegravir (DTG)-containing simplified dual combination antiretroviral therapy (cART) and traditional triple cART for people living with HIV/AIDS. The meta-analysis of randomized controlled trials compared DTG-containing dual therapy with triple cART. The primary outcome was virologic suppression. The secondary outcomes included CD4T cell recovery, lipids change from baseline, and adverse events (AEs). A total of 7 studies, 4852 patients were eligible, 2423 (49.9%) received DTG-based simplified dual cART, and 2429 (50.1%) received triple cART. The viral suppression rate was 94.7% at 24 weeks, 93.0% at 48 weeks, and 96.6% at 96 weeks in dual cART. The viral suppression rate of dual cART was non-inferior to triple cART at 24 weeks (risk difference [RD], -0.00; 95% confidence interval [CI] -0.02-0.01), at 48 weeks (RD, -0.01; 95% CI -0.02-0.01), and at 96 weeks (RD, -0.01; 95% CI -0.02-0.00). Sub-analysis results were consistent with the overall results. With regard to other outcomes (CD4T counts, lipids, any AEs, and AEs grade ≥ 3), there was no significant statistical difference between the two regimens. DTG-based simplified dual cART was non-inferior to triple cART in terms of efficacy and safety. This finding provides strong support for current consensus guidelines recommended the dual regimen as first-line treatment.

Integrase inhibitors versus efavirenz combination antiretroviral therapies for TB/HIV coinfection: a meta-analysis of randomized controlled trials.

BACKGROUND: Integrase inhibitors (INIs)-based antiretroviral therapies (ART) are more recommended than efavirenz (EFV)-based ART for people living with HIV/AIDS (PLWHA). Yet, the advantage of integrase inhibitors in treating TB/HIV coinfection is uncertain. Therefore, the objective of this systematic review is to evaluate the effects and safety of INIs- versus EFV-based ART in TB/HIV coinfection, and demonstrate the feasibility of the regimens. METHODS: Four electronic databases were systematically searched through September 2020. Fixed-effects models were used to calculate pooled effect size for all outcomes. The primary outcomes were virologic suppression and bacteriology suppression for INIs- versus EFV-based ART. Secondary outcomes included CD4+ cell counts change from baseline, adherence and safety. RESULTS: Three trials (including 672 TB/HIV patients) were eligible. ART combining INIs and EFV had similar effects for all outcomes, with none of the point estimates argued against the INIs-based ART on TB/HIV patients. Compared to EFV-based ART as the reference group, the RR was 0.94 (95% CI 0.85 to 1.05) for virologic suppression, 1.00 (95% CI 0.95 to 1.05) for bacteriology suppression, 0.98 (95% CI 0.95 to 1.01) for adherence. The mean difference in CD4+ cell counts increase between the two groups was 14.23 cells/µl (95% CI 0- 6.40 to 34.86). With regard to safety (adverse events, drug-related adverse events, discontinuation for drugs, grade 3-4 adverse events, IRIS (grade 3-4), and death), INIs-based regimen was broadly similar to EFV-based regimens. The analytical results in all sub-analyses of raltegravir- (RAL) and dolutegravir (DTG) -based ART were valid. CONCLUSION: This meta-analysis demonstrates similar efficacy and safety of INIs-based ART compared with EFV-based ART. This finding supports INIs-based ART as a first-line treatment in TB/HIV patients. The conclusions presented here still await further validation owing to insufficient data.

Transmission and clinical characteristics of coronavirus disease 2019 in 104 outside-Wuhan patients, China.

Cases of coronavirus disease 2019 (COVID-19) emigrating from Wuhan escalated the risk of spreading the disease in other cities. This report focused on outside-Wuhan patients to assess the transmission and clinical characteristics of this illness. Contact investigation was conducted on each patient who was admitted to the assigned hospitals in Hunan Province (geographically adjacent to Wuhan) from 22 January to 23 February 2020. Cases were confirmed by the polymerase chain reaction test. Demographic, clinical, and outcomes were collected and analyzed. Of the 104 patients, 48 (46.15%) were cases who immigrated from Wuhan; 93 (89.42%) had a definite contact history with infection. Family clusters were the major body of patients. Transmission along the chain of three "generations" was observed. Five asymptomatic infected cases were found and two of them infected their relatives. Mean age was 43 (range, 8-84) years, and 49 (47.12%) were male. The median incubation period was 6 (range, 1-32) days, which of 8 patients ranged from 18 to 32 days, 96 (92.31%) were discharged, and 1 (0.96%) died. The average hospital stay was 10 (range, 8-14) days. Family but not community transmission became the main body of infections in the two centers, suggesting the timely control measures after the Wuhan shutdown worked well. Asymptomatic transmission demonstrated here warned us that it may lead to the widespread of COVID-19. A 14-day quarantine may need to be prolonged.

Prevalence of HIV-1 Drug-Resistance Genotypes Among Unique Recombinant Forms from Yunnan Province, China in 2016-2017.

To investigate the prevalence and characteristics of drug-resistance genotypes among unique recombinant forms (URFs) in HIV-1 infected people under long-term antiretroviral treatment failure from Yunnan Province. The plasma samples were collected from antiretroviral therapy (ART)-failure experienced individuals from 2016 to 2017 in Yunnan Province, China. The genotyping drug resistance of HIV-1 pol gene fragments was implemented using in-house assay. According to the analysis of RIP and MEGA 7.0, the HIV-1 strains related to URFs were screened for recombinant identification and drug resistance analysis. A total of 130 pol sequences of HIV-1 URF strains were obtained from 1,121 samples. The proportion of HIV-1 URF strains was 11.6% among the ART-failure individuals from 2016 to 2017 in Yunnan. The overall drug-resistance rate of HIV-1 URF strains was 56.9%. Meanwhile, the percentage of protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) resistance was 3.8% (5/130), 36.2% (47/130), and 53.8% (70/130), respectively. Mutations such as M184V/I (35.4%) in NRTIs and K103N/R/S/T (25.4%), V179D/E/T/Y (18.9%), G190A/E/R/S (13.8%), and Y181C (9.2%) in NNRTIs were common among the HIV-1 URF strains relative to other mutations. Factors such as male, sexual transmission pathway, and source of the year 2017 were significantly correlated with the development of HIV-1 URF drug resistance. The emergence of the multiple recombinant forms identified in Yunnan indicates active transmission networks of HIV-1 of different HIV-1 subtype/circulating recombinant forms cross-infection in this region. Therefore, it is necessary to further monitor the molecular epidemiology and drug resistance of HIV-1 in Yunnan.