Development and validation of novel interpretable survival prediction models based on drug exposures for severe heart failure during vulnerable period.

BACKGROUND: Severe heart failure (HF) has a higher mortality during vulnerable period while targeted predictive tools, especially based on drug exposures, to accurately assess its prognoses remain largely unexplored. Therefore, this study aimed to utilize drug information as the main predictor to develop and validate survival models for severe HF patients during this period. METHODS: We extracted severe HF patients from the MIMIC-IV database (as training and internal validation cohorts) as well as from the MIMIC-III database and local hospital (as external validation cohorts). Three algorithms, including Cox proportional hazards model (CoxPH), random survival forest (RSF), and deep learning survival prediction (DeepSurv), were applied to incorporate the parameters (partial hospitalization information and exposure durations of drugs) for constructing survival prediction models. The model performance was assessed mainly using area under the receiver operator characteristic curve (AUC), brier score (BS), and decision curve analysis (DCA). The model interpretability was determined by the permutation importance and Shapley additive explanations values. RESULTS: A total of 11,590 patients were included in this study. Among the 3 models, the CoxPH model ultimately included 10 variables, while RSF and DeepSurv models incorporated 24 variables, respectively. All of the 3 models achieved respectable performance metrics while the DeepSurv model exhibited the highest AUC values and relatively lower BS among these models. The DCA also verified that the DeepSurv model had the best clinical practicality. CONCLUSIONS: The survival prediction tools established in this study can be applied to severe HF patients during vulnerable period by mainly inputting drug treatment duration, thus contributing to optimal clinical decisions prospectively.

The benefit of omeprazole exposure on all-cause mortality and length of ICU/hospital stay might vary with age in critically ill pediatric patients: A cohort study.

PURPOSE: To investigate the association between proton pump inhibitors (PPIs) administration during hospitalization and mortality and length of stay in critically ill pediatric patients. MATERIALS AND METHODS: This is a retrospective observational cohort study on pediatric ICU patients (0 to 18 years). Propensity score matching (PSM), Kaplan-Meier curves, Cox proportional hazards model and Linear regression model was applied for assessing the effects of PPIs on mortality and other outcomes during hospitalization. RESULTS: A total of 2269 pediatric ICU patients were included, involving 1378 omeprazole (OME) users and 891 non-OME users. The results showed significant association between OME exposure and decreased ICU stay (ß -0.042; 95% CI -0.073--0.011; P = 0.008) but prolonged non-ICU hospital stay (ß 0.121; 95% CI 0.097-0.155; P = 0.040). No statistical significance was observed between OME exposure and reduced mortality, but the OME group had a slightly decreased tendency in 28-day mortality (HR 0.701; 95% CI 0.418-1.176) and in-hospital mortality (HR 0.726; 95% CI 0.419-1.257). Furthermore, subgroup analyses revealed that the decreased tendency of mortality were more obvious in patients less than 1 year old compared with older pediatric patients, although not statistically significant. In addition, we also observed that OME exposure was significantly associated with reduced mortality of general ICU subgroup. CONCLUSIONS: This study provided a sign that PPIs used only in the ICU, rather than throughout hospital stay, might provide more benefit for critically ill pediatric patients. Additionally, younger pediatric patients might gain relatively more benefit than older children when receiving PPIs.

Short-term usage of proton pump inhibitors during admission was associated with increased risk of rehospitalization in critically ill patients with myocardial infarction: a cohort study.

PURPOSE: Previous studies showed that long-term use of proton pump inhibitors (PPIs) was associated with cardiovascular events. However, the impact of short-term PPI exposure on intensive care unit (ICU) patients with myocardial infarction (MI) remains largely unknown. This study aims to determine the precise correlation between short-term PPI usage during hospitalization and prognostic outcomes of ICU-admitted MI patients using Medical Information Mart for Intensive Care IV database (MIMIC-IV). METHODS: Propensity score matching (PSM) was applied to adjust confounding factors. The primary study outcome was rehospitalization with mortality and length of stay as secondary outcomes. Binary logistic, multivariable Cox, and linear regression analyses were employed to estimate the impact of short-term PPI exposure on ICU-admitted MI patients. RESULTS: A total of 7249 patients were included, involving 3628 PPI users and 3621 non-PPI users. After PSM, 2687 pairs of patients were matched. The results demonstrated a significant association between PPI exposure and increased risk of rehospitalization for MI in both univariate and multivariate [odds ratio (OR) = 1.157, 95% confidence interval (CI) 1.020-1.313] analyses through logistic regression after PSM. Furthermore, this risk was also observed in patients using PPIs > 7 days, despite decreased risk of all-cause mortality among these patients. It was also found that pantoprazole increased the risk of rehospitalization, whereas omeprazole did not. CONCLUSION: Short-term PPI usage during hospitalization was still associated with higher risk of rehospitalization for MI in ICU-admitted MI patients. Furthermore, omeprazole might be superior to pantoprazole regarding the risk of rehospitalization in ICU-admitted MI patients.

A meta-analysis of associations of IL-10 gene polymorphisms with acute leukemia susceptibility.

BACKGROUND: Recently, increasing evidence has demonstrated that IL-10 single nucleotide polymorphisms (SNPs) are associated with the risk of acute leukemia (AL), but the findings of different articles remain controversial. Thus, we performed a meta-analysis to further investigate the exact roles of IL-10 SNPs in AL susceptibility. METHODS: Six common Chinese and English databases were utilized to retrieve eligible studies. The strength of the association was assessed by calculating odds ratios and 95 % confidence intervals. All analyses were carried out using Review Manager (version 5.3) and STATA (version 15.1). The registered number of this research is CRD42022373362. RESULTS: A total of 6391 participants were enrolled in this research. The results showed that the AG genotype of rs1800896 increased AL risk in the heterozygous codominant model (AG vs. AA, OR = 1.41, 95 % CI = 1.04-1.92, P = 0.03) and overdominant model (AG vs. AA + GG, OR = 1.32, 95 % CI = 1.04-1.70, P = 0.03). In the subgroup analysis, associations between the G allele, GG genotype, AG genotype, AG + GG genotype of rs1800896 and increased AL risk were also observed in the mixed population based on allelic, homozygote codominant, heterozygous codominant, dominant, and overdominant models. Furthermore, an association between the AC genotype of rs1800872 and increased AL risk was observed in the Caucasian population in the overdominant model. However, the rs1800871, rs3024489 and rs3024493 polymorphisms did not affect AL risk. CONCLUSION: IL-10 rs1800896 and rs1800872 affected the susceptibility of AL and therefore may be biomarkers for early screening and risk prediction of AL.

Generation and identification of endothelial-specific Hrh2 knockout mice.

Histamine H2 receptor (HRH2) is closely associated with the development of cardiovascular and cerebrovascular diseases. However, systematic Hrh2 knockout mice did not exactly reflect the HRH2 function in specific cell or tissue types. To better understand the physiological and pathophysiological functions of endothelial HRH2, this study constructed a targeting vector that contained loxp sites flanking the ATG start codon located in Hrh2 exon 2 upstream and a neomycin (Neo) resistance gene flanked by self-deletion anchor sites within the mouse Hrh2 allele. The targeting vector was then electroporated into C57BL/6J embryonic stem (ES) cells, and positively targeted ES cell clones were micoinjected into C57BL/6J blastocysts, which were implanted into pseudopregnant females to obtain chimeric mice. The F1 generation of Hrh2flox/+ mice was generated via crossing chimeric mice with wild-type mice to excise Neo. We also successfully generated endothelial cell-specific knockout (ECKO) mice by crossing Hrh2flox/+ mice with Cdh5-Cre mice that specifically express Cre in endothelial cells and identified that Hrh2 deletion was only observed in endothelial cells. Hrh2flox/+ and Hrh2ECKO mice were normal, healthy and fertile and did not display any obvious abnormalities. These novel animal models will create new prospects for exploring roles of HRH2 during the development and treatment of related diseases.

The Associations Between CYP2D6*10 C188T Polymorphism and Pharmacokinetics and Clinical Outcomes of Tramadol: A Systematic Review and Meta-analysis.

BACKGROUND: Tramadol is one of the most extensively used centrally acting synthetic opioid analgesics. Recently, a number of studies have explored the associations of the CYP2D6*10 C188T polymorphism with pharmacokinetic and clinical outcomes of tramadol. However, the results of these previous reports remain controversial. Therefore, a meta-analysis was needed to reach a consensus. METHODS: PubMed, EMBASE, and the Cochrane Library were searched to identify eligible studies that explored the influence of the CYP2D6*10 C188T polymorphism on clinical outcomes of tramadol through April 2019. Articles meeting the inclusion criteria were comprehensively reviewed by two independent evaluators. A meta-analysis was performed using Review Manager 5.3. RESULTS: A total of nine studies involving 809 related subjects were included in this meta-analysis. Significant associations were found between CYP2D6*10 C188T mutation and longer serum tramadol half-lives, larger AUC0-∞, and the slower clearance rate of tramadol. In addition, we also found that CYP2D6*10 C188T had effects on the pharmacokinetic parameters of the metabolite of tramadol, O-desmethyltramadol, by sensitive analysis. Furthermore, CYP2D6*10 C188T polymorphism was associated with higher visual analog scale score, loading dose, and total consumption of tramadol. There was no significant association between CYP2D6*10 C188T polymorphism and postoperative nausea and vomiting. CONCLUSIONS: CYP2D6*10 C188T polymorphism had a significant influence on tramadol pharmacokinetics and analgesic effect, but there was insufficient evidence to demonstrate that this polymorphism was associated with incidence of nausea and vomiting.

The associations of HLA-DRB1 gene polymorphisms with late-onset myasthenia gravis: a meta-analysis.

BACKGROUND: Late-onset myasthenia gravis (LOMG) is one of the major subgroups of the MG. Intensive evidence suggested that polymorphisms in HLA-DRB1 gene were associated with LOMG risk, but the results remained inconsistent. Therefore, a meta-analysis is conducted to make a more precise evaluation between HLA-DRB1 alleles and LOMG. METHODS: The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure (CNKI), and Wan Fang and Technology of Chongqing (VIP) Database were searched for eligible studies. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were applied to assess the association between HLA-DRB1 alleles and LOMG. RESULTS: A total of 11 studies involving 5513 people were included in our meta-analysis. The results showed that DRB1 07 and 0403 alleles were risk factors for LOMG (1.83 [1.12, 2.98], P = 0.02; 7.05 [2.62, 18.92], P = 0.0001, respectively), while DRB1 0301 and 1301 alleles were identified as protective factors for LOMG (0.44 [0.31, 0.62], P < 0.00001; 0.38 [0.23, 0.62], P = 0.0001, respectively). As for the HLA-DRB1 04 and 14 alleles, our subgroup analysis showed that there were significant associations between these alleles and LOMG in Caucasians (2.21 [1.14, 4.27], P = 0.02; 2.82 [1.29, 6.14], P = 0.009, respectively). CONCLUSIONS: These results confirmed the association of DRB1 alleles (0301, 04, 0403, 07, 1301, and 14) and LOMG, which might provide potential promising biomarkers for prediction of LOMG risk.

The associations of CYP19A1 rs700518 polymorphism with bone mineral density and risk of osteoporosis: a meta-analysis.

Osteoporosis is now a worldwide public health problem that seriously endangers human health, but its causes have not yet been fully clarified. Recently, increasing evidence suggested that polymorphisms in CYP19A1 gene were associated with osteoporosis risk and bone mineral density (BMD), but results remained conflicting. We herein performed a meta-analysis based on evidence currently available from the literature to make a more precise estimation of these relationships. The PubMed, Embase, Cochrane library, CNKI (China National Knowledge Infrastructure), and Wan Fang databases were searched for eligible studies. Odds ratio (OR), mean difference (MD), and 95% confidence interval (CI) were applied to assess the strength of these relationships. A total of 8 studies involving 2632 subjects were included in our meta-analysis. We observed that the AG genotype of CYP19A1 rs700518 was significantly associated with lower BMD values of lumbar spine and femoral neck (AG vs. GG: p = .001 and.01, respectively). However, this polymorphism had no obvious impacts on osteoporosis risk according to current available data. In conclusion, the present meta-analysis showed that CYP19A1 rs700518 polymorphism may be a potential candidate biomarker for osteoporosis screening, early diagnosis, and treatment, which will help improve individualized therapy of osteoporosis patients in clinics.

The Associations Between CYP2D6 Metabolizer Status and Pharmacokinetics and Clinical Outcomes of Venlafaxine: A Systematic Review and Meta-Analysis.

BACKGROUND: The association between CYP2D6 metabolizer status and clinical outcomes of venlafaxine was extensively investigated previously, but no widely accepted conclusion has been reached so far. To obtain a more precise estimation of the association, a systematic review by meta-analysis was conducted in the present study. METHODS: The PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Technology of Chongqing, and Wan Fang Database were searched for eligible studies up to August 2018. RESULTS: Fourteen related studies involving 1035 patients were finally included. Significant associations were found among 3 CYP2D6 phenotypes (NM, IM, and PM) and most pharmacokinetic parameters of venlafaxine. However, CYP2D6 phenotypes were not associated with Hamilton Depression Rating Scale response of venlafaxine. In addition, we also found no significant association between CYP2D6 phenotype and overall rate of adverse events. CONCLUSIONS: CYP2D6 metabolizer status had significant influence on venlafaxine pharmacokinetics, but insufficient evidence demonstrated that CYP2D6 metabolizer status was associated with its therapeutic effects and overall rate of adverse events, which provided further evidence regarding the relationship between CYP2D6 metabolizer status and venlafaxine.

Effect of UGT2B7 genotypes on plasma concentration of valproic acid: a meta-analysis.

PURPOSE: Valproic acid (VPA) is one of the most widely used antiepileptic drugs. Recently, increasing evidence suggested that polymorphisms in UGT2B7 gene were associated with VPA pharmacokinetics, but results remained controversial. Therefore, a meta-analysis was performed to derive a more precise evaluation between C802T, C161T, and G211T polymorphisms and plasma concentration of VPA. METHODS: The PubMed, EMBASE, and the Cochrane library databases were searched for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated. The mean difference (MD) and 95% confidence interval (CI) were applied to assess the strength of the relationship. RESULTS: A total of 12 studies involving 1996 related East Asia epilepsy patients were assessed. We found that the UGT2B7 G211T polymorphism was associated with adjusted plasma VPA concentration (GG versus TT: P = 0.01, I 2 = 97%; GG versus GT: P < 0.00001, I 2 = 0%). Additionally, we also observed a significantly association between the C161T polymorphism and adjusted plasma VPA concentration (CC versus CT: P = 0.01, I 2 = 77%). Nevertheless, the pooled analysis showed that the C802T polymorphism had no significant effect on adjusted serum concentration of VPA. CONCLUSIONS: The results of this meta-analysis demonstrated that UGT2B7 G211T and C161T polymorphisms were able to affect the pharmacokinetics in epilepsy patients treated with VPA, which provide further evidence for genetic effects of UGT2B7 gene on pharmacokinetics and pharmacodynamics of VPA. Epilepsy patients with these genotypes may be necessary to increase (or decrease) VPA dose to ensure its therapeutic effect.

The HRH4 rs11662595 mutation is associated with histamine H4 receptor dysfunction and with increased epithelial-to-mesenchymal transition progress in non-small cell lung cancer.

We previously demonstrated that histamine H4 receptor (HRH4) played important roles to suppress epithelial-to-mesenchymal transition (EMT) progress in non-small cell lung cancer (NSCLC). Furthermore, recent investigations suggested that genetic variations in HRH4 gene affected HRH4 function and eventually contributed to certain HRH4-related diseases. However, the relations between polymorphisms in HRH4 gene and NSCLC as well as their underlying mechanisms remain largely uninvestigated. This study aims to investigate the genetic effect of a nonsynonymous HRH4 polymorphism (rs11662595) on HRH4 function and its association with NSCLC both basically and clinically. For basic experiments, A549 cells were transfected with either wild type or rs11662595 mutated HRH4 clone and subjected to both in vitro and in vivo experiments. We showed that rs11662595 significantly decreased the ability of HRH4 to activate Gi protein, which resulted in facilitation of EMT progress, cell proliferation, and invasion behavior in vitro. Moreover, in vivo experiments also showed that rs11662595 attenuated the anti-EMT effects of HRH4 agonist in inoculated nu/nu mice. For clinical experiments, we performed a prospective cohort study among 624 NSCLC patients and further proved that rs11662595 was responsible for the prognosis, degree of malignancy and metastasis of NSCLC. In conclusion, these findings reveal that rs11662595 is a loss-of-function polymorphism that results in dysfunction of HRH4 and attenuates the anti-EMT function of HRH4 in NSCLC, which provides a promising biomarker for prognosis and therapy of NSCLC.

Lack of Association between rs2067474 Polymorphism in Histamine Receptor H2 Gene and Breast Cancer in Chinese Han Population.

Histamine H2 receptor (HRH2) was previously suggested to affect the proliferation of breast cancer cells and disease-free survival of breast cancer patients. Furthermore, a common polymorphism, rs2067474, was identified in an enhancer element of the HRH2 gene promoter and was reported to be associated with various diseases including cancer. However, the relationship between this polymorphism and breast cancer risk and malignant degree remains unclear. The aim of this study was to clarify the clinical association of rs2067474 polymorphism with breast cancer. A total of 201 unrelated Chinese Han breast cancer patients and 238 ethnicity-matched health controls were recruited and rs2067474 polymorphism was genotyped. Logistic regression analyses were performed to calculate the odds ratios (ORs) as a measure of association of genotype with breast cancer according to 3 genetic models (dominant, recessive, and additive). Although the percentage of hormone receptor negative cases tended to be higher in AA genotypes, we did not find any significant associations of rs2067474 polymorphism with breast cancer risk or with related clinicopathological parameters in the present study, which indicates that rs2067474 polymorphism of HRH2 gene might not be a risk factor in the development of breast cancer in Chinese Han population.

Development and validation of an LC-ESI-MS/MS method for the quantitation of hemslecin A in rhesus monkey plasma and its application in pharmacokinetics.

In this study, a new LC-ESI-MS/MS-based method was validated for the quantitation of hemslecin A in rhesus monkey plasma using otophylloside A as internal standard (IS). Hemslecin A and the IS were extracted from rhesus monkey plasma using liquid-liquid extraction as the sample clean-up procedure, and were subjected to chromatography on a Phenomenex Luna CN column (150 × 2.0 mm, 3.0 µm) with the mobile phase consisting of methanol and 0.02 mol/mL ammonium acetate (55:45, v/v) at a flow rate of 0.2 mL/min. Detection was performed on an Agilent G6410B tandem mass spectrometer by positive ion electrospray ionization in multiple reaction monitoring mode, monitoring the transitions m/z 580.5 [M + NH4 ](+) → 503.4 and m/z 518.2 [M + NH4 ](+) → 345.0 for hemslecin A and IS, respectively. The assay was linear over the concentration range of 0.5-200 ng/mL and was successfully applied to a pharmacokinetic study in rhesus monkeys.

The adenosine deaminase gene polymorphism is associated with chronic heart failure risk in Chinese.

Adenosine (Ado) is an important cardioprotective agent. Since endogenous Ado levels are affected by the enzyme Ado deaminase (ADA), polymorphisms within the ADA gene may exert some effect on chronic heart failure (CHF). This study applied a case-control investigation to 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls in which nine single-nucleotide polymorphisms (SNPs) of ADA were genotyped and association analyses were performed. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the association. Overall, rs452159 polymorphism in ADA gene was significantly associated with susceptibility to CHF under the dominant model (p = 0.013, OR = 1.537, 95% CI = 1.10-2.16), after adjustment for age, sex, and traditional cardiovascular risk factors. No difference in genotype distribution and allele frequency for the rs452159 according to the functional New York Heart Association class was found. Furthermore, the values of left ventricular ejection fraction, left-ventricle end-diastolic diameter or left-ventricle end-systolic diameter did not differ significantly among the different rs452159 genotype CHF patients. Although further studies with larger cohorts and other ethnicities are required to validate the conclusions, the findings of this study potentially provide novel insight into the pathogenesis of CHF.

Effect of Histamine H2 Receptor Antagonists on All-Cause Mortality in Critically Ill Patients With Essential Hypertension: A Retrospective Cohort Study.

Previous studies found that histamine H2 receptor antagonists (H2RAs) had blood pressure lowering and cardioprotective effects, but the impact of H2RAs on the survival outcomes of critically ill patients with essential hypertension is still unclear. The aim of this study was to investigate the association of H2RAs exposure with all-cause mortality in patients with essential hypertension based on Medical Information Mart for Intensive Care III database. A total of 17,739 patients were included, involving 8482 H2RAs users and 9257 non-H2RAs users. Propensity score matching (PSM) was performed to improve balance between 2 groups that were exposed to H2RAs or not. Kaplan-Meier survival curves were used to compare the cumulative survival rates and multivariable Cox regression models were performed to evaluate the association between H2RAs exposure and all-cause mortality. After 1:1 PSM, 4416 pairs of patients were enrolled. The results revealed potentially significant association between H2RAs exposure and decreased 30-day, 90-day, and 1-year mortalities in multivariate analyses (HR = 0.783, 95% CI: 0.696-0.882 for 30-day; HR = 0.860, 95% CI: 0.778-0.950 for 90-day; and HR = 0.883, 95% CI: 0.811-0.961 for 1-year mortality, respectively). Covariate effect analyses showed that the use of H2RAs was more beneficial in essential hypertension patients with age ≥ 60, BMI ≥ 25 kg/m2, coronary arteriosclerosis, stroke, and acute kidney failure, respectively. In conclusion, H2RAs exposure was related to lower mortalities in critically ill patients with essential hypertension, which provided novel potential strategy for the use of H2RAs in essential hypertension patients.

Up-regulation of NDRG2 through nuclear factor-kappa B is required for Leydig cell apoptosis in both human and murine infertile testes.

Many pro-apoptotic factors, such as nuclear factor-kappa B (NF-κB) and Fas, play crucial roles in the process of Leydig cell apoptosis, ultimately leading to male sterility, such as in Sertoli cell only syndrome (SCO) and hypospermatogenesis. However, the molecular mechanism of such apoptosis is unclear. Recent reports on N-myc downstream-regulated gene 2 (ndrg2) have suggested that it is involved in cellular differentiation, development, and apoptosis. The unique expression of NDRG2 in SCO and hypospermatogenic testis suggests its pivotal role in those diseases. In this study, we analyzed NDRG2 expression profiles in the testes of normal spermatogenesis patients, hypospermatogenesis patients, and SCO patients, as well as in vivo and in vitro models, which were Sprague-Dawley rats and the Leydig cell line TM3 treated with the Leydig cell-specific toxicant ethane-dimethanesulfonate (EDS). Our data confirm that NDRG2 is normally exclusively located in the cytoplasm of Leydig cells and is up-regulated and translocates into the nucleus under apoptotic stimulations in human and murine testis. Meanwhile, transcription factor NF-κB was activated by EDS administration, bound to the ndrg2 promoter, and further increased in expression, effects that were abolished by NF-κB inhibitor Pyrrolidine dithiocarbamate (PDTC). Furthermore, siRNA knock-down of ndrg2 led to increased proliferative or decreased apoptotic TM3 cells, while over-expression of ndrg2 had the reverse effect. This study reveals that ndrg2 is a novel gene that participates in Leydig cell apoptosis, with essential functions in testicular cells, and suggests its possible role in apoptotic Leydig cells and male fertility.

Histamine H2 receptor antagonist exhibited comparable all-cause mortality-decreasing effect as ß-blockers in critically ill patients with heart failure: a cohort study.

Background: Our previous study reported that histamine H2 receptor antagonists (H2RAs) exposure was associated with decreased mortality in critically ill patients with heart failure (HF) through the same pharmacological mechanism as ß-blockers. However, population-based clinical study directly comparing the efficacy of H2RAs and ß-blockers on mortality of HF patients are still lacking. This study aims to compare the association difference of H2RAs and ß-blockers on mortality in critically ill patients with HF using the Medical Information Mart for Intensive Care III database (MIMIC-III). Methods: Study population was divided into 4 groups: ß-blockers + H2RAs group, ß-blockers group, H2RAs group, and Non-ß-blockers + Non-H2RAs group. Kaplan-Meier curves and multivariable Cox regression models were employed to evaluate the differences of all-cause mortalities among the 4 groups. Propensity score matching (PSM) was used to increase comparability of four groups. Results: A total of 5593 patients were included. After PSM, multivariate analyses showed that patients in H2RAs group had close all-cause mortality with patients in ß-blockers group. Furthermore, 30-day, 1-year, 5-year and 10-year all-mortality of patients in ß-blockers + H2RAs group were significantly lower than those of patients in ß-blockers group, respectively (HR: 0.64, 95%CI: 0.50-0.82 for 30-day; HR: 0.80, 95%CI: 0.69-0.93 for 1-year mortality; HR: 0.83, 95%CI: 0.74-0.93 for 5-year mortality; and HR: 0.85, 95%CI: 0.76-0.94 for 10-year mortality, respectively). Conclusion: H2RAs exposure exhibited comparable all-cause mortality-decreasing effect as ß-blockers; and, furthermore, H2RAs and ß-blockers had additive or synergistic interactions to improve survival in critically ill patients with HF.

Comparative efficacy and safety of uricosuric agents in the treatment of gout or hyperuricemia: a systematic review and network meta-analysis.

OBJECTIVES: The current world witnesses a greatly increased prevalence and incidence of hyperuricemia and gout with unfortunately the comparative efficacy and safety of present available uricosuric agents remaining uncertain. We herein aimed to investigate the most appropriate uricosuric agent for gout or hyperuricemia patients. METHOD: PubMed, Embase, Cochrane Library databases, and ClinicalTrials.gov from inception to 2 July 2022 were searched to retrieve eligible studies assessing efficacy and safety of uricosuric drugs in hyperuricemia or gout patients. Network meta-analysis was carried out using the Stata 16.0 software. RESULTS: Twelve randomized controlled trials comprising 1851 patients were eventually included. Network meta-analysis showed that dotinurad 4 mg once daily, verinurad, dotinurad 2 mg once daily, dotinurad 1 mg once daily, and benzbromarone were the top 5 effective treatments to achieve target serum uric acid. Furthermore, dotinurad 4 mg once daily was more effective at achieving urate-lowering targets (RR of dotinurad 4 mg once daily vs. probenecid: 1.68, 95% CI [1.13; 2.50]) and safer (RR of probenecid vs. dotinurad 4 mg once daily: 1.77, 95% CI [0.69; 4.56]) than probenecid. CONCLUSIONS: This network meta-analysis demonstrated an important absolute benefit of dotinurad 4 mg once daily to achieve target serum uric acid and low risk of adverse events for drug treatment of gout or hyperuricemia patients. Additionally, verinurad might be used as an alternative uricosuric therapeutic option to dotinurad. These findings provided further comprehensive insight into the treatment value of current uricosuric agents for gout or hyperuricemia. Key Points 1. This is the first systematic review and network meta-analysis examining the efficacy and safety of currently available uricosuric agents in gout or hyperuricemia patients. 2. Recommended doses of dotinurad 4mg once daily used for the treatment of gout or hyperuricemia patients can significantly decrease serum uric acid levels. 3. The present findings will provide further comprehensive insight into the treatment value of certain uricosuric agents for gout or hyperuricemia.

Effectiveness and Safety of Histamine H2 Receptor Antagonists: An Umbrella Review of Meta-Analyses.

Histamine H2 receptor antagonists (H2RAs) were widely used to inhibit gastric acid secretion, but its association with adverse events remains controversial and unclear. We conducted an umbrella review of meta-analyses to systematically assess the quality and credibility of the correlations between H2RA use with the risk of adverse outcomes through searching 4 major databases from inception to April 30, 2022. Forty-six individual meta-analyses were identified, including 29 meta-analyses of observation studies with 32 unique outcomes and 19 meta-analyses of randomized controlled trials with 3 unique outcomes for comparing the H2RA versus non-H2RA group. A Measurement Tool to Assess Systematic Reviews 2 rating for the included meta-analyses showed that 4 of 46 meta-analyses were assigned as high scores, 3 were assigned as "moderate," and 25 were assigned as low scores. Grading of Recommendations Assessment, Development and Evaluation assessment for combined results demonstrated that 6 outcomes were rated as "moderate," 9 outcomes were rated as "low," and 17 outcomes were rated as "very low." We confirmed significant associations of H2RA use with pneumonia, peritonitis, necrotizing enterocolitis, Clostridium difficile infection, liver cancer, gastric cancer, and hip fracture diseases. No associations for colorectal cancer, melanoma, kidney cancer, lung cancer, or common reproductive system cancer or renal, neurological, and cardiovascular system diseases were observed. We found a variety of evidence for the associations between H2RAs and adverse outcomes, which would give clinicians more positive guidance on prescription of H2RAs in clinical practice.

Scutellarin inhibits cytochrome P450 isoenzyme 1A2 (CYP1A2) in rats.

Scutellarin is the most important flavone glycoside in the herbal drug Erigeron breviscapus (Vant.) Hand.-Mazz. It is used frequently in the clinic to treat ischemic vascular diseases in China. However, the direct relationship between scutellarin and cytochrome P450 (CYP450) is unclear. The present study investigated the in vitro and in vivo effects of scutellarin on cytochrome P450 1A2 (CYP 1A2) metabolism. According to in vitro experiments, scutellarin (10-250 µM) decreased the formation of 4-acetamidophenol in a concentration-dependent manner, with an IC50 value of 108.20 ± 0.657 µM. Furthermore, scutellarin exhibited a weak mixed-type inhibition against the activity of CYP1A2 in rat liver microsomes, with a K(i) value of 95.2 µM. Whereas in whole animal studies, scutellarin treatment for 7 days (at 5, 15, 30 mg/kg, i.p.) decreased the clearance (CL), and increased the T(1/2) (at 15, 30 mg/kg, i.p.), it did not affect the V(d) of phenacetin. Scutellarin treatment (at 5, 15, 30 mg/kg, i.p.) increased the AUC(0-∞) by 14.3%, 67.3% and 159.2%, respectively. Scutellarin at 30 mg/kg also weakly inhibited CYP1A2 activity, in accordance with our in vitro study. Thus, the results indicate that CYP1A2 is inhibited directly, but weakly, by scutellarin in vivo, and provide useful information on the safe and effective use of scutellarin in clinical practice.