Association of stage 1 hypertension defined by the 2017 ACC/AHA guideline with cardiovascular events and mortality in Chinese adults.

BACKGROUND: The 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guideline lowered the threshold defining hypertension to 130/80 mmHg. However, how stage 1 hypertension defined using this guideline is associated with cardiovascular events in Chinese adults remains unclear. This study assessed the association between stage 1 hypertension defined by the 2017 ACC/AHA guideline and clinical outcomes in the Chinese population. METHODS: Participants with stage 1 hypertension ( n = 69,509) or normal BP ( n = 34,142) were followed in this study from 2006/2007 to 2020. Stage 1 hypertension was defined as a systolic blood pressure of 130-139 mmHg or a diastolic blood pressure of 80-89 mmHg. None were taking antihypertensive medication or had a history of myocardial infarction (MI), stroke, or cancer at baseline. The primary outcome was a composite of MI, stroke, and all-cause mortality. The secondary outcomes were individual components of the primary outcome. Cox proportional hazards models were used for the analysis. RESULTS: During a median follow-up of 11.09 years, we observed 10,479 events (MI, n = 995; stroke, n = 3408; all-cause mortality, n = 7094). After multivariable adjustment, the hazard ratios for stage 1 hypertension vs. normal BP were 1.20 (95% confidence interval [CI], 1.13-1.25) for primary outcome, 1.24 (95% CI, 1.05-1.46) for MI, 1.45 (95% CI, 1.33-1.59) for stroke, and 1.11 (95% CI, 1.04-1.17) for all-cause mortality. The hazard ratios for participants with stage 1 hypertension who were prescribed antihypertensive medications compared with those without antihypertensive treatment during the follow-up was 0.90 (95% CI, 0.85-0.96). CONCLUSIONS: Using the new definition, Chinese adults with untreated stage 1 hypertension are at higher risk for MI, stroke, and all-cause mortality. This finding may help to validate the new BP classification system in China.

Safety and immunogenicity of the COVID-19 mRNA vaccine CS-2034: A randomized, double-blind, dose-exploration, placebo-controlled multicenter Phase I clinical trial in healthy Chinese adults.

BACKGROUND: The novel coronavirus pneumonia (COVID-19) is an infectious disease caused by the infection of a novel coronavirus known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has resulted in millions of deaths. We aimed to evaluate the safety and immunogenicity of the COVID-19 mRNA vaccine (CS-2034, CanSino, Shanghai, China) in adults without COVID-19 infection from China. METHOD: This is a multicenter Phase I clinical trial with a randomized, double-blinded, dose-exploration, placebo-controlled design. The trial recruited 40 seronegative participants aged 18-59 years who had neither received any COVID-19 vaccine nor been infected before. They were divided into a low-dose group (administered with either the CS-2034 vaccine containing 30 µg of mRNA or a placebo of 0.3 ml type 5 adenovirus vector) and a high-dose group (administered with either the CS-2034 vaccine containing 50 µg of mRNA or a placebo of 0.5 ml type 5 adenovirus vector). Participants were randomly assigned in a 3:1 ratio to receive either the mRNA vaccine or a placebo on days 0 and 21 according to a two-dose immunization schedule. The first six participants in each dosage group were assigned as sentinel subjects. Participants were sequentially enrolled in a dose-escalation manner from low to high dose and from sentinel to non-sentinel subjects. Blood samples were collected from all participants on the day before the first dose (Day 0), the day before the second dose (day 21), 14 days after the second dose (day 35), and 28 days after the second dose (day 49) to evaluate the immunogenicity of the CS-2034 vaccine. Participants were monitored for safety throughout the 28-day follow-up period, including solicited adverse events, unsolicited adverse events, adverse events of special interest (AESI), and medically attended adverse events (MAE). This report focuses solely on the safety and immunogenicity analysis of adult participants aged 18-59 years, while the long-term phase of the study is still ongoing. This study is registered at ClinicalTrials.gov, NCT05373485. FINDINGS: During the period from May 17, 2022, to August 8, 2022, a total of 155 participants aged 18-59 years were screened for this study. Among them, 115 participants failed the screening process, and 40 participants were randomly enrolled (15 in the low-dose group, 15 in the high-dose group, and 10 in the placebo group). Throughout the 28-day follow-up period, the overall incidence of adverse reactions (related to vaccine administration) in the low-dose group, high-dose group, and placebo group was 93.33% (14/15), 100.00% (15/15), and 80.00% (8/10), respectively. There was a statistically significant difference in the incidence of local adverse reactions (soreness, pruritus, swelling at the injection site) among the low-dose group, high-dose group, and placebo group (P = 0.002). All adverse reactions were mainly of severity grade 1 (mild) or 2 (moderate), and no adverse events of severity grade 4 or higher occurred. Based on the analysis of Spike protein Receptor Binding Domain (S-RBD) IgG antibodies against the BA.1 strain, the seroconversion rates of antibodies at day 21 after the first dose were 86.67%, 93.33%, and 0.00% in the low-dose group, high-dose group, and placebo group, respectively. The geometric mean titer (GMT) of antibodies was 61.2(95%CI 35.3-106.2), 55.4(95%CI 36.3-84.4), and 15.0(95%CI 15.0-15.0), and the geometric mean fold increase (GMI) was 4.08(95%CI 2.35-7.08), 3.69(95%CI 2.42-5.63), and 1.00(95%CI 1.00-1.00) for each group. At day 28 after the full vaccination, the seroconversion rates of antibodies were 100.00%, 93.33%, and 0.00%, and the GMT of antibodies was 810.0(95%CI 511.4-1283.0), 832.2(95%CI 368.1-1881.6), and 15.0(95%CI 15.0-15.0), and the GMI was 54.00(95%CI 34.09-85.53), 55.48(95%CI 24.54-125.44), and 1.00(95%CI 1.00-1.00) for each group, respectively. Based on the analysis of CD3+/CD4+ cell cytokine response, the percentages of IL-2+, IL-4+, IFN-γ+, and TNF-α+ cells increased after 14 days and 28 days of full vaccination in both the low-dose group and high-dose group. The increase was most pronounced in the high-dose group. INTERPRETATION: At day 28 after the full vaccination, both the low-dose and the high-dose CS-2034 vaccine were able to induce the production of high titers of S-RBD IgG antibodies against the BA.1 strain. Adverse reactions in the low-dose and high-dose groups were mainly of severity grade 1 or 2, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine.

Severity of non-alcoholic fatty liver disease is a risk factor for developing hypertension from prehypertension.

BACKGROUND: There is little published evidence about the role of non-alcoholic fatty liver disease (NAFLD) in the progression from prehypertension to hypertension. This study was conducted to investigate the association of NAFLD and its severity with the risk of hypertension developing from prehypertension. METHODS: The study cohort comprised 25,433 participants from the Kailuan study with prehypertension at baseline; those with excessive alcohol consumption and other liver diseases were excluded. NAFLD was diagnosed by ultrasonography and stratified as mild, moderate, or severe. Univariable and multivariable Cox proportional hazard regression was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) of incident hypertension according to the presence and 3 categories of severity of NAFLD. RESULTS: During a median of 12.6 years of follow-up, 10,638 participants progressed to hypertension from prehypertension. After adjusting for multiple risk factors, patients with prehypertension and NAFLD had a 15% higher risk of incident hypertension than those without NAFLD (HR = 1.15, 95% CI 1.10-1.21). Moreover, the severity of NAFLD was associated with the incidence of hypertension, which was higher in patients with more severe NAFLD (HR = 1.15 [95% CI 1.10-1.21] in the mild NAFLD group; HR = 1.15 [95% CI 1.07-1.24] in the moderate NAFLD group; and HR = 1.20 [95% CI 1.03-1.41] in the severe NAFLD group). Subgroup analysis indicated that age and baseline systolic blood pressure may modify this association. CONCLUSIONS: NAFLD is an independent risk factor for hypertension in patients with prehypertension. The risk of incident hypertension increases with the severity of NAFLD.

Alterations of Gut Microbiome, Metabolome, and Lipidome in Takayasu Arteritis.

OBJECTIVE: Mounting evidence has linked microbiome and metabolome to systemic autoimmunity and cardiovascular diseases (CVDs). Takayasu arteritis (TAK) is a rare disease that shares features of immune-related inflammatory diseases and CVDs, about which there is relatively limited information. This study was undertaken to characterize gut microbial dysbiosis and its crosstalk with phenotypes in TAK. METHODS: To address the discriminatory signatures, we performed shotgun sequencing of fecal metagenome across a discovery cohort (n = 97) and an independent validation cohort (n = 75) including TAK patients, healthy controls, and controls with Behçet's disease (BD). Interrogation of untargeted metabolomics and lipidomics profiling of plasma and fecal samples were also used to refine features mediating associations between microorganisms and TAK phenotypes. RESULTS: A combined model of bacterial species, including unclassified Escherichia, Veillonella parvula, Streptococcus parasanguinis, Dorea formicigenerans, Bifidobacterium adolescentis, Lachnospiraceae bacterium 7 1 58FAA, Escherichia coli, Streptococcus salivarius, Klebsiella pneumoniae, Bifidobacterium longum, and Lachnospiraceae Bacterium 5 1 63FAA, distinguished TAK patients from controls with areas under the curve (AUCs) of 87.8%, 85.9%, 81.1%, and 71.1% in training, test, and validation sets including healthy or BD controls, respectively. Diagnostic species were directly or indirectly (via metabolites or lipids) correlated with TAK phenotypes of vascular involvement, inflammation, discharge medication, and prognosis. External validation against publicly metagenomic studies (n = 184) on hypertension, atrial fibrillation, and healthy controls, confirmed the diagnostic accuracy of the model for TAK. CONCLUSION: This study first identifies the discriminatory gut microbes in TAK. Dysbiotic microbes are also linked to TAK phenotypes directly or indirectly via metabolic and lipid modules. Further explorations of the microbiome-metagenome interface in TAK subtype prediction and pathogenesis are suggested.

Kidney microbiota dysbiosis contributes to the development of hypertension.

Gut microbiota dysbiosis promotes metabolic syndromes (e.g., hypertension); however, the patterns that drive hypertensive pathology and could be targeted for therapeutic intervention are unclear. We hypothesized that gut microbes might translocate to the kidney to trigger hypertension. We aimed to uncover their method of colonization, and thereby how to maintain blood pressure homeostasis. Using combined approaches based on fluorescence in situ hybridization (FISH) and immunofluorescence staining, electron microscopy analysis, bacterial cultures, species identification, and RNA-sequencing-based meta-transcriptomics, we first demonstrated the presence of bacteria within the kidney of spontaneously hypertensive rats (SHRs) and its normotensive counterpart, Wistar-Kyoto rats (WKYs), and patients with hypertension. Translocated renal bacteria were coated with secretory IgA (sIgA) or remained dormant in the L-form. Klebsiella pneumoniae (K.pn) was identified in the kidneys of germ-free (GF) mice following intestinal transplantation, which suggested an influx of gut bacteria into the kidneys. Renal bacterial taxa and their function are associated with hypertension. Hypertensive hosts showed increased richness in the pathobionts of their kidneys, which were partly derived from the gastrointestinal tract. We also demonstrated the indispensable role of bacterial IgA proteases in the translocation of live microbes. Furthermore, Tartary buckwheat dietary intervention reduced blood pressure and modulated the core renal flora-host ecosystem to near-normal states. Taken together, the unique patterns of viable and dormant bacteria in the kidney provide insight into the pathogenesis of non-communicable chronic diseases and cardiometabolic diseases (e.g., hypertension), and may lead to potential novel microbiota-targeted dietary therapies.

Identification of the hub and prognostic genes in liver hepatocellular carcinoma via bioinformatics analysis.

Hepatocellular carcinoma (HCC) is a common malignancy. However, the molecular mechanisms of the progression and prognosis of HCC remain unclear. In the current study, we merged three Gene Expression Omnibus (GEO) datasets and combined them with The Cancer Genome Atlas (TCGA) dataset to screen differentially expressed genes. Furthermore, protein‒protein interaction (PPI) and weighted gene coexpression network analysis (WGCNA) were used to identify key gene modules in the progression of HCC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that the terms were associated with the cell cycle and DNA replication. Then, four hub genes were identified (AURKA, CCNB1, DLGAP5, and NCAPG) and validated via the expression of proteins and transcripts using online databases. In addition, we established a prognostic model using univariate Cox proportional hazards regression and least absolute shrinkage and selection operator (LASSO) regression. Eight genes were identified as prognostic genes, and four genes (FLVCR1, HMMR, NEB, and UBE2S) were detrimental gens. The areas under the curves (AUCs) at 1, 3 and 5 years were 0.622, 0.69, and 0.684 in the test dataset, respectively. The effective of prognostic model was also validated using International Cancer Genome Consortium (ICGC) dataset. Moreover, we performed multivariate independent prognostic analysis using multivariate Cox proportional hazards regression. The results showed that the risk score was an independent risk factor. Finally, we found that all prognostic genes had a strong positive correlation with immune infiltration. In conclusion, this study identified the key hub genes in the development and progression of HCC and prognostic genes in the prognosis of HCC, which was significant for the future diagnosis and prognosis of HCC.

Causality of Opportunistic Pathogen Klebsiella pneumoniae to Hypertension Development.

BACKGROUND: Previous studies have reported a strong association between gut microbiome and hypertension; yet, the exact bacterial species associated with the disease development and progression have not yet been detected. This study aimed to investigate whether opportunistic pathogen Klebsiella pneumoniae is a causal factor for hypertension pathogenesis, and explore the potential mechanisms. METHODS: The enrichment of Klebsiella pneumoniae in the gut of patients with hypertension was validated by meta-analysis based on 3 independent cohorts. Klebsiella pneumoniae was inoculated into germ-free mice, antibiotic pretreated and conventional mice. RESULTS: Klebsiella pneumoniae led to higher blood pressure, slight cardiac hypertrophy, and enhanced contractility of resistant arteries in recipient mice. Moreover, Klebsiella pneumoniae induced pathological damages, deficiency of tight junction proteins and transcriptional shifts. Metabolic alterations, especially the depletion of stearoylethanolamide, were observed upon Klebsiella pneumoniae administration. In addition, renal transcriptome dysfunction with significant upregulation of genes related to hypertension pathogenesis was observed in Klebsiella pneumoniae treated mice. CONCLUSIONS: These results provide evidence that the enrichment of Klebsiella pneumoniae acts as a direct contributor to blood pressure elevation and hypertension pathogenesis, and Klebsiella pneumoniae induced intestinal damages, fecal metabolic changes, and renal shifts may be integrated mediators.

Causal associations between disorders of lipoprotein metabolism and ten cardiovascular diseases.

Disorders of lipoprotein metabolism have been linked with an increased risk of cardiovascular diseases (CVDs) but the causal association is unclear. In this study, we investigated the causal association between disorders of lipoprotein metabolism and CVDs using two-sample Mendelian randomization (MR). The exposure was obtained from Finn genome-wide association studies (14,010 cases, 197,259 controls), and the corresponding CVDs were extracted from the largest published genome-wide association studies. A random-effects inverse-variance weighted method was used for the main analyses with a complementary analysis using the weighted median and MR-Egger approaches. Multiple sensitivity analyses were performed to assess horizontal pleiotropy. The MR analysis indicated positive associations of disorders of lipoprotein metabolism with coronary artery disease (odds ratio [OR] 1.670, 95% confidence interval [CI] 1.373-2.031; p < 0.001), aortic aneurysm (OR 1.394, 95% CI 1.199-1.619; p < 0.001), heart failure (OR 1.20, 95% CI 1.115-1.294; p < 0.001), hypertension (OR 1.011, 95% CI 1.006-1.091; p < 0.001), old myocardial infarction (OR 1.004, 95% CI 1.002-1.007; p = 0.001), and stroke (OR 1.002, 95% CI 1.001-1.003; p = 0.002). There is a suggestive causal relationship between disorders of lipoprotein metabolism and atrial fibrillation (OR 1.047, 95% CI 1.006-1.091; p = 0.026) and acute myocardial infarction (OR 1.003, 95% CI 1.001-1.005; p = 0.012). There was limited evidence of a causal association between disorders of lipoprotein metabolism and peripheral vascular disease and venous thromboembolism. Our findings indicate a significant causal association between disorders of lipoprotein metabolism and many CVDs, including coronary artery disease, aortic aneurysm, heart failure, hypertension, old myocardial infarction, and stroke. These associations may be useful for development of treatment strategies that regulate lipoprotein metabolism in patients with CVD.

Severity of Nonalcoholic Fatty Liver Disease is Associated With Cardiovascular Outcomes in Patients With Prehypertension or Hypertension: A Community-Based Cohort Study.

Background: It is unclear whether more severe non-alcoholic fatty liver disease (NAFLD) combined with prehypertension or hypertension is associated with a higher risk of cardiovascular events (CVEs). To evaluate the relationship between the severity of NAFLD and CVEs among patients with prehypertension or hypertension. Methods: In this prospective community-based Kailuan cohort, participants without cardiovascular disease and alcohol abuse, or other liver diseases were enrolled. NAFLD was diagnosed by abdominal ultrasonography. Prehypertension was defined as systolic blood pressure (BP) of 120-139 mmHg or diastolic BP of 80-89 mmHg. Participants with NAFLD were divided into mild, moderate, and severe subgroups. Follow-up for CVEs including myocardial infarction, hemorrhagic stroke, and ischemic stroke. The Cox proportional hazards model was used to estimate hazard ratios and 95% CIs of CVEs according to the severity of NAFLD and hypertensive statutes. The C-statistic was used to evaluate the efficiency of models. Results: A total of 71926 participants (mean [SD] age, 51.83 [12.72] years, 53794 [74.79%] men, and 18132 [25.21%] women) were enrolled in this study, 6,045 CVEs occurred during a median of 13.02 (0.65) years of follow-up. Compared with participants without NAFLD, the hazard ratios of CVEs for patients with mild, moderate, and severe NAFLD were 1.143 (95% CI 1.071-1.221, P < 0.001), 1.218 (95% CI 1.071-1.221, P < 0.001), and 1.367 (95% CI 1.172-1.595, P < 0.001), respectively. Moreover, participants with prehypertension plus moderate/severe NAFLD and those with hypertension plus moderate/severe NAFLD had 1.558-fold (95% CI 1.293-1.877, P < 0.001) and 2.357-fold (95% CI 2.063-2.691, P < 0.001) higher risks of CVEs, respectively, compared with those with normal BP and no NAFLD. Adding a combination of NAFLD and BP status to the crude Cox model increased the C-statistic by 0.0130 (0.0115-0.0158, P < 0.001). Conclusions: Our findings indicated that the increased cardiovascular risk with elevated BP is largely driven by the coexistence of moderate/severe NAFLD, suggesting that the severity of NAFLD may help further stratify patients with prehypertension and hypertension.

Diagnostic and prognostic predictive values of triggering receptor expressed on myeloid cell-1 expression in neonatal sepsis: A meta-analysis and systematic review.

Objective: The purpose of this systematic review was to explore the value of the expression level of the triggering receptor expressed on myeloid cell-1 (TREM-1) in the diagnosis and prognosis of neonatal sepsis. Methods: A comprehensive search was performed to identify the diagnostic and prognostic predictive values of the TREM-1 expression level in neonatal sepsis. Based on the retrieval strategy, Cochrane Library, Embase, Ovid, ProQuest, PubMed, Scopus, and Web of Science databases were searched from inception to February 2022. Studies were included if they assessed the accuracy of TREM-1 expression in the diagnosis of neonatal sepsis and distinguished survival and death in neonatal sepsis. Two authors independently evaluated the study and extracted the data, including the first author of the literature, country, total study population, basic population characteristics of the study group and the control group, study design (observational studies), type of sample, sepsis onset, type of biomarker, assay method, cut-off, sensitivity, specificity, true positives (TP), false positives (FP), false negatives (FN), and true negatives (TN). A third party will be consulted if disputed. The accuracy of TREM-1 expression in the diagnosis and prognostic prediction of neonatal sepsis was evaluated by a bivariate mixed-effects model. The source of heterogeneity was explored through meta-regression analysis. Results: Thirteen articles that met the research criteria were included in qualitative analysis, and 11 of them were included in quantitative analysis. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the summary receiver operator characteristic (SROC) curve of soluble TREM-1 (sTREM-1) were 0.94 (95% CI: 0.82, 0.98), 0.87 (95% CI: 0.70, 0.95), 7.36 (95% CI: 2.75, 19.74), 0.07 (95% CI: 0.02, 0.24), 111.71 (95% CI: 13.24, 942.92), and 0.96 (95% CI: 0.94, 0.98), respectively. Meta-regression and subgroup analysis were used to investigate the heterogeneity, owing to non-threshold effects caused by types of test sample and research design. sTREM-1 as a biomarker for distinguishing survival and death in neonates with sepsis had pooled sensitivity, specificity, area under the SROC curve, PLR, NLR, and DOR of 0.95 (95% CI: 0.83, 0.99), 0.98 (95% CI: 0.68, 1.00), 0.99 (95% CI: 0.97, 0.99), 39.28 (95% CI: 2.13, 723.99), 0.05 (95% CI: 0.01, 0.19), and 789.61 (95% CI: 17.53, 35,560.72), respectively. Conclusion: The study showed that TREM-1 was a potential biomarker for the diagnosis and prognosis of neonatal sepsis. The biggest advantage of this study is that it is the first to comprehensively explore the role of TREM-1 expression in the diagnosis and prognosis of neonatal sepsis. However, there are some limitations in this study, such as the reduced number of clinical studies on TREM-1 expression as a biomarker of neonatal sepsis, regional bias, and differences in detection methods. Hence, more large-scale and high-quality studies are needed to improve diagnostic accuracy. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022338041.

Pre-miRNA Hsa-Let-7a-2: a Novel Intracellular Partner of Angiotensin II Type 2 Receptor Negatively Regulating its Signals.

G protein-coupled receptors (GPCRs) are the largest family of druggable targets, and their biological functions depend on different ligands and intracellular interactomes. Some microRNAs (miRNAs) bind as ligands to RNA-sensitive toll-like receptor 7 to regulate the inflammatory response, thereby contributing to the pathogenesis of cancer or neurodegeneration. It is unknown whether miRNAs bind to angiotensin II (Ang II) type 2 receptor (AGTR2), a critical protective GPCR in cardiovascular diseases, as ligands or intracellular interactomes. Here, screening for miRNAs that bind to AGTR2, we identified and confirmed that the pre-miRNA hsa-let-7a-2 non-competitively binds to the intracellular third loop of AGTR2. Functionally, intracellular hsa-let-7a-2 overexpression suppressed the Ang II-induced AGTR2 effects such as cAMP lowering, RhoA inhibition, and activation of Src homology 2 domain-containing protein-tyrosine phosphatase 1, whereas hsa-let-7a-2 knockdown enhanced these effects. Consistently, overexpressed hsa-let-7a-2 restrained the AGTR2-induced antiproliferation, antimigration, and proapoptosis of cells, and vasodilation of mesenteric arteries. Our findings demonstrated that hsa-let-7a-2 is a novel intracellular partner of AGTR2 that negatively regulates AGTR2-activated signals.

[Therapeutic effect of hydrocortisone combined with vitamin C and vitamin B1 on patients with sepsis: a Meta-analysis].

OBJECTIVE: To systematically evaluate the effect of hydrocortisone combined with vitamin C and vitamin B1 on the efficacy of patients with sepsis or septic shock. METHODS: Databases including CNKI, Sino Med, VIP, Wanfang, PubMed, the Cochrane Library, and Embase were searched from inception to January 2021 for the randomized controlled trial (RCT) about hydrocortisone combined with vitamin C and vitamin B1 to treat sepsis or septic shock. The experimental group was given intravenous injection of hydrocortisone, vitamin B1 and vitamin C based on conventional treatment; the control group was given conventional treatment or placebo/hydrocortisone/hydrocortisone+vitamin B1 based on conventional treatment. Outcome indicators included sequential organ failure assessment (SOFA), mortality, the duration of vasoactive drugs, new acute kidney injury (AKI) patients, length of stay in intensive care unit (ICU) and in hospital. Two researchers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. RevMan 5.3 software was then used to perform Meta-analysis. Funnel plot was used to test publication bias. RESULTS: A total of 6 articles involving 816 patients were included, with 411 patients in the experimental group and 405 patients in the control group. The Meta-analysis results showed that the duration of vasoactive drugs in the experimental group was significantly shorter than that in the control group [mean difference (MD) = -24.02, 95% confidence interval (95%CI) was -32.36 to -15.68, P < 0.000 01]. However, there were no significant differences in SOFA, mortality, new AKI patients, the length of ICU stay and hospital stay between the two groups [SOFA: MD = -0.14, 95%CI was -1.15 to 0.87, P = 0.79; mortality: relative risk (RR) = 0.99, 95%CI was 0.81 to 1.21, P = 0.92; new AKI patients: RR = 1.10, 95%CI was 0.42 to 2.87, P = 0.84; length of ICU stay: MD = 1.33, 95%CI was -2.22 to 4.89, P = 0.46; length of hospital stay: MD = 1.02, 95%CI was -0.66 to 2.69, P = 0.23]. The funnel plot showed that most of the points were symmetrical and showed an inverted funnel shape, suggesting that the publication bias among the studies was small. There was no significant publication bias on this Meta-analysis. CONCLUSIONS: Hydrocortisone combined with vitamin C and vitamin B1 can shorten the duration of vasoactive drugs in patients with sepsis or septic shock, but it cannot effectively reduce the SOFA score, mortality, new AKI patients, length of stay in ICU and in hospital. Limited by the number and quality of the included studies, further large-scale, multi-center, blinded, RCT are still needed for verification.

Evaluating the spectrum-effect profiling and pharmacokinetics of Tieshuang Anshen Prescription with better sedative-hypnotic effect based on Fe2+ than Hg2.

Although Zhusha Anshen Pill (ZSASP) is a commonly used traditional prescription for insomnia, the safety of cinnabar in the formula has always been controversial since its initial application in medical fields. Here, we developed a new prescription, Tieshuang Anshen Prescription (TSASP), by improving ZSASP with Fe2+ instead of Hg2+. Besides, TSASP was further optimized by establishing and testing the HPLC fingerprint and its sedative-hypnotic effect of formulas with different compatibility ratios and performing correlation spectrum analysis. The safety of TSASP was also evaluated by HE staining of liver and kidney. In addition, a validated and robust UHPLC-MS/MS method was established to demonstrate the pharmacokinetic characteristics of berberine, palmatine, jatrorrhizine, ligustilide, catalpol, loganin, liquiritin and liquiritigenin after oral administration of TSASP. Our study originally provides a new non-toxic prescription, TSASP, with better sedative-hypnotic effect in comparison with ZSASP, revealing that Fe2+ could replace Hg2+ to eliminate its toxicity and play a sedative role. Meanwhile, we believe that our pharmacokinetics results may contribute valuable reference to both TSASP's specific mechanism of action and its further clinical efficacy and effectiveness research.

Single cell transcriptomic analysis identifies novel vascular smooth muscle subsets under high hydrostatic pressure.

Although some co-risk factors and hemodynamic alterations are involved in hypertension progression, their direct biomechanical effects are unclear. Here, we constructed a high-hydrostatic-pressure cell-culture system to imitate constant hypertension and identified novel molecular classifications of human aortic smooth muscle cells (HASMCs) by single-cell transcriptome analysis. Under 100-mmHg (analogous to healthy human blood pressure) or 200-mmHg (analogous to hypertension) hydrostatic pressure for 48 h, HASMCs showed six distinct vascular SMC (VSMC) clusters according to differential gene expression and gene ontology enrichment analysis. Especially, two novel HASMC subsets were identified, named the inflammatory subset, with CXCL2, CXCL3 and CCL2 as markers, and the endothelial-function inhibitory subset, with AKR1C2, AKR1C3, SERPINF1 as markers. The inflammatory subset promoted CXCL2&3 and CCL2 chemokine expression and secretion, triggering monocyte migration; the endothelial-function inhibitory subset secreted SERPINF1 and accelerated prostaglandin F2α generation to inhibit angiogenesis. The expression of the two VSMC subsets was greatly increased in arterial media from patients with hypertension and experimental animal models of hypertension. Collectively, we identified high hydrostatic pressure directly driving VSMCs into two new subsets, promoting or exacerbating endothelial dysfunction, thereby contributing to the pathogenesis of cardiovascular diseases.

New drug targets for hypertension: A literature review.

Hypertension is one of the most prevalent cardiovascular diseases worldwide. However, in the population of resistant hypertension, blood pressure is difficult to control effectively. Moreover, antihypertensive drugs may have adverse effect currently. Hence, new therapeutic targets and treatments are needed to uncovered and exploited to control hypertension and its comorbidities. In the past, classical drug targets, such as the aldosterone receptor, aldosterone synthase, and ACE2/angiotensin 1-7/Mas receptor axis, have been investigated. Recently, vaccines and drugs targeting the gastrointestinal microbiome, which represent drug classes, have also been investigated for the management of blood pressure. In this review, we summarized current knowledge on classical and new drug targets and discussed the potential utility of new drugs in the treatment of hypertension.

The Role of Exosomal microRNAs and Oxidative Stress in Neurodegenerative Diseases.

Neurodegenerative diseases including Alzheimer's disease and Parkinson's disease are aging-associated diseases with irreversible damage of brain tissue. Oxidative stress is commonly detected in neurodegenerative diseases and related to neuronal injury and pathological progress. Exosome, one of the extracellular vesicles, is demonstrated to carry microRNAs (miRNAs) and build up a cell-cell communication in neurons. Recent research has found that exosomal miRNAs regulate the activity of multiple physiological pathways, including the oxidative stress response, in neurodegenerative diseases. Here, we review the role of exosomal miRNAs and oxidative stress in neurodegenerative diseases. Firstly, we explore the relationship between oxidative stress and neurodegenerative diseases. Secondly, we introduce the characteristics of exosomes and roles of exosome-related miRNAs. Thirdly, we summarized the crosstalk between exosomal miRNAs and oxidative stress in neurodegenerative diseases. Fourthly, we discuss the potential of exosomes to be a biomarker in neurodegenerative diseases. Finally, we summarize the advantages of exosome-based delivery and present situation of research on exosome-based delivery of therapeutic miRNA. Our work is aimed at probing and reinforcing the recognition of the pathomechanism of neurodegenerative diseases and providing the basis for novel strategies of clinical diagnosis and treatment.

Automated long-term monitoring of parallel microfluidic operations applying a machine vision-assisted positioning method.

As microfluidics has been applied extensively in many cell and biochemical applications, monitoring the related processes is an important requirement. In this work, we design and fabricate a high-throughput microfluidic device which contains 32 microchambers to perform automated parallel microfluidic operations and monitoring on an automated stage of a microscope. Images are captured at multiple spots on the device during the operations for monitoring samples in microchambers in parallel; yet the device positions may vary at different time points throughout operations as the device moves back and forth on a motorized microscopic stage. Here, we report an image-based positioning strategy to realign the chamber position before every recording of microscopic image. We fabricate alignment marks at defined locations next to the chambers in the microfluidic device as reference positions. We also develop image processing algorithms to recognize the chamber positions in real-time, followed by realigning the chambers to their preset positions in the captured images. We perform experiments to validate and characterize the device functionality and the automated realignment operation. Together, this microfluidic realignment strategy can be a platform technology to achieve precise positioning of multiple chambers for general microfluidic applications requiring long-term parallel monitoring of cell and biochemical activities.