Interleukin-19 enhances eosinophil infiltration through upregulation of epithelium-derived RANTES expression via the ERK/NF-κB signalling pathway in patients with eosinophilic CRSwNP.

BACKGROUD: The recurrence rate of chronic rhinosinusitis with nasal polyps (CRSwNP) is positively correlated with eosinophil infiltration. Increased interleukin (IL)-19 and eosinophil chemokine RANTES levels have been reported in patients with CRSwNP. This study aimed to clarify the role of IL-19 in mediating RANTES expression and eosinophilic infiltration in eosinophilic CRSwNP (Eos CRSwNP). METHODS: Nasal tissue samples were obtained from patients with CRSwNP and controls. The expression of IL-19, its receptors, ECP, and RANTES in tissues was investigated. Primary human nasal epithelial cells (HNECs) and nasal polyp tissue blocks were cultured, then stimulated by IL-19; ERK phosphorylation, NF-κB pathway activation, RANTES level, eosinophils migration and infiltration were detected using RT-qPCR, ELISA, western blotting, HE, immunohistochemistry, immunofluorescence staining, confocal microscopy, and transwell migration assay. RESULTS: The expression of IL-19 and its receptors (IL-20R1/IL-20R2), eosinophil cationic protein, and RANTES in nasal tissues from patients with Eos CRSwNP was significantly increased compared to that in non-Eos CRSwNP and control subjects. IL-19 co-localized with RANTES in nasal tissues and significantly elevated RANTES expression in HNECs. IL-19-blocking antibody and siRNA knockdown of IL-20R1 ameliorated the effect of IL-19 on RANTES secretion in HNECs. Moreover, IL-19-induced RANTES upregulation was associated with the activation of the ERK and NF-κB pathways. NF-κB activation was mediated by the ERK pathway in IL-19-treated HNECs, and IL-19 enhanced eosinophil infiltration in nasal polyp tissue blocks. CONCLUSIONS: Our findings indicate that IL-19 promotes RANTES expression via the ERK/NF-κB pathway in HNECs and is implicated in eosinophil infiltration in patients with Eos CRSwNP.

IL-21 induces pyroptosis of Treg cells via Akt-mTOR-NLRP3-caspase 1 axis in eosinophilic chronic rhinosinusitis.

BACKGROUND: Regulatory T (Treg) cells, which prevent inflammation-induced eosinophil infiltration, are deficient in nasal polyps (NPs) in patients with eosinophilic chronic rhinosinusitis (ECRS). It is concomitant with loss of Foxp3 after certain inflammatory stimuli. OBJECTIVE: We sought to determine the inflammatory cytokines involved in inducing the loss of Treg cells in NPs. METHODS: The abundance of cytokines in ECRS patients or mice were tested using ELISA, immunochemistry, immunofluorescence, quantitative reverse transcription PCR (qPCR), and/or flow cytometry. Expression of eosinophil cationic protein (ECP), CD4+ T cells, IL-4, and IL-17A and eosinophils in nasal mucosa of mouse model was investigated by immunochemistry, immunofluorescence, and hematoxylin and eosin staining. The percentage and death of induced Treg (iTreg) cells, source of IL-21 in NPs from ECRS and non-ECRS patients, and abundance of different systemic phenotypes of CD4+ T cells in a mouse model were studied by flow cytometry. Western blot analysis, scanning, and transmission electronic microscopy were used to detect pyroptosis of iTreg cells. RESULTS: IL-21 was highly expressed in nasal mucosa of ECRS patients and mice, causing pyroptosis and preventing development of iTreg cells in vitro. The elevated IL-21 in NPs from ECRS patients was mainly produced by CD3+ T cells, including T follicular helper, T peripheral helper, TH2, and TH17 cells and CD3+CD4- T cells. T peripheral helper cells and CD3+CD4- T cells were the predominant source of IL-21 in NPs from non-ECRS patients. Blocking IL-21/IL-21R signaling significantly reduced the number of eosinophils and CD4+ T cells along with ECP, IL-4, and IL-17A expression in the nasal mucosa of ECRS mice. It also increased Treg cell percentage and systemically decreased TH2 and TH17 ratios. Akt-mTOR inhibition prevented IL-21-induced pyroptosis in human and mouse iTreg cells. CONCLUSION: Elevated IL-21 drives pyroptosis and prevents Treg cell development in ECRS patients. IL-21 induced pyroptosis via activating Akt-mTOR-NLRP3-caspase 1 signaling.

Efficacy of Glycyrrhetinic Acid in the Treatment of Acne Vulgaris Based on Network Pharmacology and Experimental Validation.

Glycyrrhetinic acid (GA) is a saponin compound, isolated from licorice (Glycyrrhiza glabra), which has been wildly explored for its intriguing pharmacological and medicinal effects. GA is a triterpenoid glycoside displaying an array of pharmacological and biological activities, including anti-inflammatory, anti-bacterial, antiviral and antioxidative properties. In this study, we investigated the underlying mechanisms of GA on acne vulgaris through network pharmacology and proteomics. After the intersection of the 154 drug targets and 581 disease targets, 37 therapeutic targets for GA against acne were obtained. A protein-protein interaction (PPI) network analysis highlighted TNF, IL1B, IL6, ESR1, PPARG, NFKB1, STAT3 and TLR4 as key targets of GA against acne, which is further verified by molecular docking. The experimental results showed that GA inhibited lipid synthesis in vitro and in vivo, improved the histopathological damage of skin, prevented mast cell infiltration and decreased the level of pro-inflammatory cytokines, including TNF-α, IL-1ß and IL-6. This study indicates that GA may regulate multiple pathways to improve acne symptoms, and the beneficial effects of GA against acne vulgaris might be through the regulation of sebogenesis and inflammatory responses.

IL-17A mediates pyroptosis via the ERK pathway and contributes to steroid resistance in CRSwNP.

BACKGROUND: Pyroptosis is closely related to inflammation. However, the molecular mechanisms and pathologic contributions of pyroptotic epithelial cell are not yet fully understood. OBJECTIVE: This study aimed to explore the function and molecular mechanisms of IL-17A on human nasal epithelial cell (hNEC) pyroptosis. METHODS: The expression of pyroptosis-related biomarkers and IL-17A was assessed in sinonasal mucosa from control individuals, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic rhinosinusitis with nasal polyps (CRSwNP) by using quantitative RT-PCR. Their localization was analyzed via immunohistochemistry and immunofluorescence. The ultrastructural characteristics of IL-17A-induced pyroptosis in hNECs were visualized by using electron microscopy. IL-17A functional assays were performed on hNECs and airway epithelial cell lines. Cytokine levels were quantified via ELISA. The signaling pathways involved in IL-17A-induced pyroptosis were studied via unbiased RNA sequencing and Western blotting. RESULTS: The expression of IL-17A and the pyroptotic biomarkers NOD-like receptor family, pyrin domain containing 3 (NLRP3), caspase-1, gasdermin D, and IL-1ß was increased in nasal mucosa from patients with CRSwNP compared with in those with chronic rhinosinusitis without nasal polyps and the control subjects. IL-17A was positively correlated and colocalized with the pyroptotic biomarkers. IL-17A treatment induced pyroptosis in the hNECs and cell lines analyzed, primarily through the extracellular signal-regulated kinase (ERK)-NLRP3/caspase-1 signaling pathway, and increased IL-1ß and IL-18 secretion in hNECs. Moreover, IL-17A-induced pyroptosis contributed to steroid resistance by affecting glucocorticoid receptor-α and glucocorticoid receptor-ß expression, and the inhibition of pyroptotic proteins partially abolished IL-17A-induced steroid resistance in hNECs. CONCLUSION: Elevated IL-17A level promotes pyroptosis in hNECs through the ERK-NLRP3/caspase-1 signaling pathway and contributes to glucocorticoid resistance by affecting glucocorticoid receptor homeostasis in patients with CRSwNP.

Yes-Associated Protein and Transcriptional Coactivator with PDZ-Binding Motif in Cardiovascular Diseases.

Yes-associated protein (YAP, also known as YAP1) and its paralogue TAZ (with a PDZ-binding motif) are transcriptional coactivators that switch between the cytoplasm and nucleus and regulate the organ size and tissue homeostasis. This review focuses on the research progress on YAP/TAZ signaling proteins in myocardial infarction, cardiac remodeling, hypertension and coronary heart disease, cardiomyopathy, and aortic disease. Based on preclinical studies on YAP/TAZ signaling proteins in cellular/animal models and clinical patients, the potential roles of YAP/TAZ proteins in some cardiovascular diseases (CVDs) are summarized.

Evaluation of the TRIP13 level in breast cancer and insights into potential molecular pathways.

TRIP13 is a member of the large superfamily of the AAA + ATPase proteins and is associated with a variety of activities. Emerging evidence has shown that TRIP13 may serve as an oncogene. However, the function of TRIP13 in breast cancer (BC) has not yet been elucidated. Here, a variety of bioinformatic tools and laboratory experiments were combined to analyse the expression patterns, prognostic value and functional network of TRIP13 in BC. Multiple databases and immunohistochemistry (IHC) indicated a higher TRIP13 expression in BC tissue compared with normal tissue. TRIP13 was highly expressed in lung metastatic lesions compared with primary tumours in a 4T1 cell implantation BALB/c mouse model of BC. Kaplan-Meier plots also revealed that high TRIP13 expression correlated with poor survival in patients with BC. Furthermore, gene set enrichment analysis revealed that TRIP13 was primarily enriched in the signalling pathway of PI3K-AKT-mTOR. Suppressing TRIP13 could inhibit the expression of related genes, as well as the proliferation and migration of BC cell. Finally, 10 hub genes with a high score of connectivity were filtered from the protein-protein interaction (PPI) network, including MAD2L1, CDC20, CDC5L, CDK1, CCNA2, BUB1B, RAD51, SPO11, KIF11 and AURKB. Thus, TRIP13 may be a promising prognostic biomarker and an effective therapeutic target for BC.

COMMD10 inhibits HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe balance in hepatocellular carcinoma.

BACKGROUND & AIMS: Copper (Cu) is an essential trace element whose serum levels have been reported to act as an effective indicator of the efficacy of radiotherapy. However, little is known about the role of Cu in radiotherapy. In this study we aimed to determine this role and investigate the precise mechanism by which Cu or Cu-related proteins regulate the radiosensitivity of hepatocellular carcinoma (HCC). METHODS: The expression and function of Cu and copper metabolism MURR1 domain 10 (COMMD10) were assessed via a Cu detection assay, immunostaining, real-time PCR, western blot, a radiation clonogenic assay and a 5-ethynyl-2'-deoxyuridine assay. Ferroptosis was determined by detecting glutathione, lipid peroxidation, malondialdehyde and ferrous ion (Fe) levels. The in vivo effects of Cu and COMMD10 were examined with Cu/Cu chelator treatment or lentivirus modification of COMMD10 expression in radiated mouse models. RESULTS: We identified a novel role of Cu in promoting the radioresistance of HCC cells. Ionizing radiation (IR) induced a reduction of COMMD10, which increased intracellular Cu and led to radioresistance of HCC. COMMD10 enhanced ferroptosis and radiosensitivity in vitro and in vivo. Mechanistically, low expression of COMMD10 induced by IR inhibited the ubiquitin degradation of HIF1α (by inducing Cu accumulation) and simultaneously impaired its combination with HIF1α, promoting HIF1α nuclear translocation and the transcription of ceruloplasmin (CP) and SLC7A11, which jointly inhibited ferroptosis in HCC cells. In addition, elevated CP promoted HIF1α expression by reducing Fe, forming a positive feedback loop. CONCLUSIONS: COMMD10 inhibits the HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe homeostasis in HCC. This work provides new targets and treatment strategies for overcoming radioresistance in HCC. LAY SUMMARY: Radiotherapy benefits patients with unresectable or advanced hepatocellular carcinoma (HCC), but its effectiveness is hampered by radioresistance. Herein, we uncovered a novel role for copper in promoting the radioresistance of HCCs. This work has revealed new targets and potential treatment strategies that could be used to sensitize HCC to radiotherapy.

A novel U-shaped relationship between mitochondrial mass and risk of incomplete immune reconstitution in HIV-infected patients on antiviral therapy.

Mitochondrial mass (MM) is considered an essential parameter of the immune system, but the association of MM with incomplete immune reconstitution (IIR) in people living with HIV (PLWH) remains unclear. Here, we tested 2148 blood samples from 1999 PLWH by flow cytometry in China between August 2021 and February 2022. A novel U-shaped relationship, determined by multivariable smooth curve fitting and piecewise-linear mixed-effect model, was observed between the ratio of MM to SD (MM/SD) and IIR, with a threshold cutoff of 2.8. For MM/SD <2.8, per SD increment of MM was independently associated with 30%, 30%, 20%, and 20% decreased risk of CD4+ T-cell counts <500 cells/µL after 4 years of treatment and CD4+ T-cell counts <350 cells/µL after 4, 5, 6 years of treatment, respectively. Our study suggested that increasing MM may indicate the low risk of IIR for PLWH with MM/SD <2.8.

Effect of probiotics on diversity and function of gut microbiota in Moschus berezovskii.

The forest musk deer, Moschus berezovskii, is a nationally protected species of economic importance in China. However, in captive breeding programmes, they usually die as a result of diarrhoea. In this study, six M. berezovskii were randomly selected and divided into two groups: probiotics group (n = 3) and placebo (control) group (n = 3). The two groups were fed a basal diet that included 2 g probiotics (probiotic group) or 2 g whey powder (placebo group) for 30 days. Faecal samples were collected at day 0, 15 and 30 and evaluated for microbial diversity, species richness and metabolic function. Probiotic intervention significantly improved gut health in M. berezovskii by changing the overall community structure of the gut microbiota. Intake of probiotics reduced the relative abundance of pathogenic bacteria such as Escherichia coli and Citrobacter freundii in the intestinal flora and increased the relative abundance of beneficial Bifidobacterium species and other lactic acid bacteria. At the same time, gut microbiota in the probiotics group were involved in regulating degradation of phenylacetic acid and in dTDP-L-rhamnose synthesis; these processes have the potential to enhance immunity in M. berezovskii. This preliminary study revealed the beneficial effects of probiotics on the gut microbiota of M. berezovskii, which the potential to significantly improve the health, wellbeing and economic value of M. berezovskii.

Expression profile of SYNE3 and bioinformatic analysis of its prognostic value and functions in tumors.

BACKGROUND: Spectrin repeat containing nuclear envelope family member 3 (SYNE3) encodes an essential component of the linker of the cytoskeleton and nucleoskeleton (LINC) complex, namely nesprin-3. In a tumor, invasiveness and metastasis rely on the integrity of the LINC complex, while the role of SYNE3/nesprin-3 in cancer is rarely studied. METHODS: Here, we explored the expression pattern, prognostic value, and related mechanisms of SYNE3 through both experimental and bioinformatic methods. We first detected SYNE3 in BALB/c mice, normal human tissues, and the paired tumor tissues, then used bioinformatics databases to verify our results. We further analyzed the prognostic value of SYNE3. Next, we predicted miRNA targeting SYNE3 and built a competing endogenous RNA (ceRNA) network and a transcriptional network by analyzing data from the cancer genome atlas (TCGA) database. Interacting genes of SYNE3 were predicted, and we further performed GO and KEGG enrichment analysis on these genes. Besides, the relationship between SYNE3 and immune infiltration was also investigated. RESULTS: SYNE3 exhibited various expressions in different tissues, mainly located on nuclear and in cytoplasm sometimes. SYNE3 expression level had prognostic value in tumors, possibly by stabilizing nucleus, promoting tumor cells apoptosis, and altering tumor microenvironment. Additionally, we constructed a RP11-2B6.2-miR-149-5p-/RP11-67L2.2-miR-330-3p-SYNE3 ceRNA network and a SATB1-miR-149-5p-SYNE3 transcriptional network in lung adenocarcinoma to support the tumor-suppressing role of SYNE3. CONCLUSIONS: Our study explored novel anti-tumor functions and mechanisms of SYNE3, which might be useful for future cancer therapy.

Angiogenic circular RNAs: A new landscape in cardiovascular diseases.

Angiogenesis refers to the formation of new blood vessels from existing blood vessels, including endothelial progenitor cells differentiation and cytokine regulation. Circular RNAs, a type of non-coding RNA, are a stable and conservative endogenous transcriptional product with a circular structure that is produced by the reverse and scrambled splicing of mRNA precursors. They can be used as microRNA sponges, are involved in transcription and protein translation, and regulate the pathophysiological processes of various diseases. Recent studies have shown that circRNAs can regulate angiogenesis by regulating vascular endothelial cell function. In this review, we summarize the angiogenic mechanism; the biogenesis, properties and biological function of circRNAs; and their roles in regulating angiogenesis. We also discuss their potential implications for clinical applications.

Retraction Note: Resveratrol rescues hyperglycemia-induced endothelial dysfunction via activation of Akt.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Prognosis and modulation mechanisms of COMMD6 in human tumours based on expression profiling and comprehensive bioinformatics analysis.

BACKGROUND: The Copper Metabolism MURR1 (COMM) domain family has been reported to play important roles in tumorigenesis. As a prototype for the COMMD family, the expression pattern and biological function of COMMD6 in human tumours remain unknown. METHODS: COMMD6 expression in BALB/c mice and human tissues was examined using real-time PCR and immunohistochemistry. Kaplan-Meier analysis was applied to evaluate the prognosis of COMMD6 in tumours. Competing endogenous RNA (ceRNA) and transcriptional regulation network were constructed based on differentially expressed mRNAs, microRNAs and long non-coding RNAs from the cancer genome atlas database. GO and KEGG enrichment analysis were used to explore the bioinformatics implication. RESULTS: COMMD6 expression was widely observed in BALB/c mice and human tissues, which predicted prognosis of cancer patients. Furthermore, we shed light on the underlying tumour promoting role and mechanism of COMMD6 by constructing a TEX41-miR-340-COMMD6 ceRNA network in head and neck squamous cell carcinoma and miR-218-CDX1-COMMD6 transcriptional network in cholangiocarcinoma. In addition, COMMD6 may modulate the ubiquitination and degradation of NF-κB subunits and regulate ribonucleoprotein and spliceosome complex biogenesis in tumours. CONCLUSIONS: This study may help to elucidate the functions and mechanisms of COMMD6 in human tumours, providing a potential biomarker for tumour prevention and therapy.

Segmentation and Diagnosis of Papillary Thyroid Carcinomas Based on Generalized Clustering Algorithm in Ultrasound Elastography.

Papillary thyroid carcinomas (PTC) are the most common type of thyroid malignant tumors. Existing methods for clustering high-noise ultrasound images tend to degrade the clustering performance. In order to realize accurate segmentation of thyroid nodule in noisy environment, this paper proposes an improved segmentation algorithm based on adaptive fast generalized clustering. Firstly, the parameter balance factor is adaptively determined according to the noise probability of non-local pixels so as to reflect the spatial structure information in the image more accurately. Then, the balance factor is used to effectively combine the linear weighted filtered image in the AFGC algorithm so as to create the adaptive filtered image. Since the filtering degree depends on the probability whether the pixel is noise in the image, the dynamic noise suppression performance of the proposed method can be greatly improved. A large number of qualitative and quantitative experimental results show that the proposed generalized clustering algorithm can obtain more accurate results when clustering images with high noise. It is suitable for intelligent diagnosis of papillary thyroid convolution in clinical examination.

Effects of mTOR/NF-κB signaling pathway and high thoracic epidural anesthesia on myocardial ischemia-reperfusion injury via autophagy in rats.

We investigated the role of mammalian target of rapamycin/nuclear factor-kappa B (mTOR/NF-κB) signaling pathway in high thoracic epidural anesthesia (HTEA) against myocardial ischemia-reperfusion (I/R) injury in rats. The rat model of myocardial I/R injury was established. Ninety rats were divided into the normal, sham, I/R, eHTEA, the PDTC, and HTEA + PDTC groups. ELISA was applied to detect cardiac function indexes. HE staining was conducted to observe histopathological changes of myocardial tissues, and TTC staining was performed to detect the myocardial infarction size. TUNEL staining was adopted to detect the cell apoptosis rate. The mRNA and protein levels of mTOR, NF-κB, Fasl, Bcl-2 and Bax, and LC3-I, LC3-II, BNIP3, and Atg5 were detected by RT-qPCR and Western blotting, respectively. The findings indicated that compared with the normal and sham groups, the I/R, PDTC, and HTEA groups showed the larger myocardial infarction size and increased cell apoptosis rate, while the results in the HTEA + PDTC group were opposite. Compared with the normal and sham groups, the I/R group showed reduced mRNA and protein levels of Bcl-2, LC3, BNIP3, and Atg5, and elevated mRNA and protein levels of mTOR, p50, p65, Bax, and Fasl, while the HTEA + PDTC group revealed the opposite results, and the PDTC and HTEA group revealed the increased mRNA and protein levels of Bcl-2, LC3, BNIP3, Atg5, mTOR, p50, p65, Bax, and Fasl. These results prove that the inhibition of mTOR/NF-κB signaling pathway potentiates HTEA against myocardial IR injury by autophagy and apoptosis in rats.

Protective Effects of Microrna-22 Against Endothelial Cell Injury by Targeting NLRP3 Through Suppression of the Inflammasome Signaling Pathway in a Rat Model of Coronary Heart Disease.

BACKGROUND/AIMS: This study aimed to identify the role of microRNA-22 (miR-22) in endothelial cell (EC) injury in coronary heart disease (CHD) by targeting NLRP3 through the inflammasome signaling pathway. METHODS: A total of 24 healthy male Sprague-Dawley (SD) rats were divided into normal and atherosclerosis groups. The atherosclerosis rats were assigned into blank, negative control (NC), miR-22 mimic, miR-22 inhibitor and miR-22 inhibitor + siNLRP3 groups. A luciferase reporter gene assay was used to detect the relationship between miR-22 and NLRP3. MiR-22 expression as well as NLRP3 and caspase-1 mRNA and protein expression were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The activity and apoptosis of coronary arterial endothelial cells (CAECs) were determined by MTT and Hoechst 33258. CAEC lumen formation was detected by a lumen formation assay. An enzyme-linked immunosorbent assay (ELISA) was used to detect IL-1ß, IL-6, IL-10 and IL-18 levels. RESULTS: The results indicated that the atherosclerosis group significantly decreased miR-22 expression but increased NLRP3 and caspase-1 mRNA and protein expression. The cell survival rate was significantly increased in the miR-22 mimic group and significantly reduced in the miR-22 inhibitor group. The miR-22 mimic group displayed a lower apoptosis rate and more cells with obvious lumen walls and numerous tubular structures, while cells in the miR-22 inhibitor group were unable to form lumen walls and had a scattered distribution compared to the blank group. The ELISA showed that IL-1ß, IL-6 and IL-18 levels were markedly decreased, while IL-10 was clearly increased in the miR-22 mimic group. In contrast, in the miR-22 inhibitor group, IL-1ß, IL-6 and IL-18 levels were significantly increased, and IL-10 levels were decreased. CONCLUSION: Our findings indicated that miR-22 could lower the levels of pro-inflammatory cytokines by inhibiting the NLRP3 inflammasome pathway, which suppresses CAEC apoptosis and protects CAECs in rats with CHD.

Is the concomitant use of clopidogrel and Proton Pump Inhibitors still associated with increased adverse cardiovascular outcomes following coronary angioplasty?: a systematic review and meta-analysis of recently published studies (2012 - 2016).

BACKGROUND: Controversies were previously observed with the concomitant use of clopidogrel and Proton Pump Inhibitors (PPIs), especially omeprazole, following coronary angioplasty. Even though several studies showed no interaction between clopidogrel and PPIs, questions have been raised about the decrease in antiplatelet effects of clopidogrel with PPIs. A previously published meta-analysis showed concomitant use of clopidogrel and PPIs to be associated with higher adverse cardiovascular outcomes. However, data which were used were extracted from studies published before the year 2012. Whether these controversies still exist in this new era is not clear. Therefore, we aim to show if the concomitant use of clopidogrel and PPIs is still associated with higher adverse outcomes following Percutaneous Coronary Intervention (PCI) using data obtained from recently published studies (2012 to 2016). METHODS: Electronic databases were searched for recent publications (2012-2016) comparing (clopidogrel plus PPIs) versus clopidogrel alone following PCI. Adverse cardiovascular outcomes were considered as the clinical endpoints. Odds Ratios (OR) with 95% Confidence Intervals (CI) were used as the statistical parameters and the pooled analyses were performed with RevMan 5.3 software. RESULTS: Eleven studies with a total number of 84,729 patients (29,235 patients from the PPIs group versus 55,494 patients from the non-PPIs group) were included. Results of this analysis showed that short term mortality and Target Vessel Revascularization (TVR) significantly favored the non-PPIs group with OR: 1.55; 95% CI: 1.43-1.68, P < 0.00001 and OR: 1.26; 95% CI: 1.06-1.49, P = 0.009 respectively. Long-term Major Adverse Cardiac Events (MACEs), Myocardial Infarction (MI), Stent Thrombosis (ST) and TVR significantly favored patients who did not use PPIs with OR: 1.37; 95% CI: 1.23-1.53, P < 0.00001, OR: 1.41; 95% CI: 1.26-1.57, P < 0.00001 and OR: 1.38; 95% CI: 1.13-1.70, P = 0.002 and OR: 1.28; 95% CI: 1.01-1.61, P = 0.04 respectively. However, the result for long term mortality was not statistically significant. CONCLUSION: The combined use of clopidogrel with PPIs is still associated with significantly higher adverse cardiovascular events such as MACEs, ST and MI following PCI supporting results of the previously published meta-analysis. However, long-term mortality is not statistically significant warranting further analysis with randomized patients.

Does infection with human immunodeficiency virus have any impact on the cardiovascular outcomes following percutaneous coronary intervention?: a systematic review and meta-analysis.

BACKGROUND: A direct link between human immunodeficiency virus (HIV)-infected patients and the risk of cardiovascular diseases (CVD) has been shown in recent scientific research. However, this issue is controversial since other previous reports showed no apparent impact of HIV or its anti-retroviral drugs on the cardiovascular system. We aimed to systematically compare the postinterventional adverse cardiovascular outcomes which were observed in patients with and without HIV infection during a mean follow up period ranging from 1 year to 3 years. METHODS: Common electronic databases were searched for studies which compared postinterventional adverse cardiovascular outcomes [mortality, myocardial infarction (MI), cardiac death, target vessel revascularization (TVR), target lesion revascularization (TLR), stroke and major adverse cardiac events (MACEs)] in patients with and without HIV infection. Statistical analysis was carried out by the RevMan 5.3 software whereby Odds Ratios (OR) and 95% Confidence Intervals (CIs) were generated. RESULTS: Two thousand two hundred and sixty-eight (2268) patients (821 patients were HIV positive and 1147 patients were HIV negative) were analyzed. The current results showed that mortality was not significantly increased among patients who were HIV positive with OR: 1.13, 95% CI: 0.65-1.96; P = 0.66. Cardiac death was also similarly reported with OR: 1.16, 95% CI: 0.50-2.68; P = 0.74. However, even if recurrent MI, TVR, TLR, MACEs and stroke were higher in patients who were HIV positive, with OR: 1.32, 95% CI: 0.88-2.12; P = 0.18, OR: 1.36, 95% CI: 0.88-2.12; P = 0.17, OR: 1.22, 95% CI: 0.72-2.06; P = 0.46, OR: 1.29, 95% CI: 0.89-1.85; P = 0.17 and OR: 1.47, 95% CI: 0.44-4.89; P = 0.53 respectively, these results were not statistically significant. CONCLUSION: Patients who were infected with HIV had similar mortality post coronary intervention compared to patients who were not infected by the virus, during a mean follow-up period of 1-3 years. In addition, no significant increase in MI, TVR, TLR, MACEs and stroke were observed during this follow up period. Therefore, it might be concluded that no apparent impact of HIV on the cardiovascular outcomes was observed post coronary intervention.

Comparing Stent Thrombosis associated with Zotarolimus Eluting Stents versus Everolimus Eluting Stents at 1 year follow up: a systematic review and meta-analysis of 6 randomized controlled trials.

BACKGROUND: Two thousand fifteen has been a winning year for Drug Eluting Stents (DES). Increase in the number of patients with cardiovascular diseases treated by Percutaneous Coronary Intervention (PCI) has resulted to a high demand for second generation DES. This current analysis aimed to compare the different types of Stent Thrombosis (ST) associated with Zotarolimus Eluting Stents (ZES) versus Everolimus Eluting Stents (EES) at 1 year follow up. METHODS: Electronic databases were searched for studies comparing ZES with EES. Different types of ST reported at 1 year follow up were considered as the primary endpoints in this analysis. Odds Ratios (OR) with 95% Confidence Intervals (CIs) were used as the statistical parameters and the pooled analyses were carried out by the RevMan 5 · 3 software. RESULTS: A total number of 10,512 patients were included in this analysis. No significant difference in any definite ST, acute definite ST, subacute definite ST, and late definite ST were observed between ZES and EES, at 1 year follow up with OR: 1.70, 95% CI: 0.92 - 3.16; P = 0.09, OR: 3.44, 95% CI: 0.82 - 14.43; P = 0.09, OR: 1.13, 95% CI: 0.43 - 2.95; P = 0.80 and OR: 2.39, 95% CI: 0.83 - 6.85; P = 0.11 respectively. Moreover, any definite or probable ST and definite/probable/possible ST were also not significantly different with OR: 1.39, 95% CI: 0.89 - 2.17; P = 0.15 and OR: 1.19, 95% CI: 0.84 - 1.70; P = 0.33 respectively. In addition, any probable ST, acute probable ST, late probable ST and possible ST were also not significantly different at 1 year follow up with OR: 1.11, 95% CI: 0.60 - 2.05; P = 0.75, OR: 0.53, 95% CI: 0.12 - 2.40; P = 0.41, OR: 1.67, 95% CI: 0.35 - 7.86; P = 0.52 and OR: 1.08, 95% CI: 0.64 - 1.82; P = 0.78 respectively. CONCLUSION: At 1 year follow up, ZES were not associated with significantly lower or higher definite and probable ST compared to EES. In addition, no significant difference was observed in acute, subacute and late definite or probable ST. However, further trials are recommended to assess the effects of these second-generation DES during the long-term.

Bleeding outcomes associated with rivaroxaban and dabigatran in patients treated for atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: Warfarin is commonly used as a secondary prevention of stroke in patients with atrial fibrillation (AF). However, limitations have been observed even with the use of this medication. Recently, several newer direct oral anticoagulants (DOACs) have been approved for use by the food and drug administrations. Unfortunately, these newer drugs have seldom been compared directly with each other. Therefore, this study aimed to compare the bleeding events associated with rivaroxaban and dabigatran in patients treated for non-valvular AF. METHODS: EMBASE, Medline (National Library of Medicine) and the Cochrane Central Registry of Controlled Trials were searched for studies comparing rivaroxaban with dabigatran using the terms 'rivaroxaban, dabigatran and atrial fibrillation'. Primary endpoints were: any bleeding outcomes, intracranial bleeding and gastro-intestinal (GI) bleeding. Secondary outcomes included stroke/systemic embolism (SE)/transient ischemic attack (TIA), venous thromboembolism and mortality. Odds ratios (OR) with 95% confidence intervals (CIs) were calculated. The pooled analyses were carried out with RevMan 5.3 software. All the authors had full access to the data and approved the manuscript as written. RESULTS: A total number of 4895 patients were included. This analysis showed that rivaroxaban was not associated with a significantly higher bleeding event when compared to dabigatran (OR: 1.28, 95% CI: 0.95-1.72; P = 0.11). GI bleeding was similarly manifested between these two DOACs (OR: 0.98, 95% CI: 0.43-2.25; P = 0.97). Even if intracranial bleeding was higher with the use of rivaroxaban, (OR: 2.18, 95% CI: 0.51-9.25; P = 0.29), the result was not statistically significant. Moreover, stroke/SE/TIA and venous thromboembolism were also not significantly different (OR: 0.81, 95% CI: 0.53-1.23; P = 0.32) and (OR: 2.06, 95% CI: 0.73-5.82; P = 0.17) respectively. However, even if mortality favored dabigatran (OR: 1.42, 95% CI: 0.99-2.06; P = 0.06), this result only approached statistical significance. CONCLUSION: Head to head comparison showed that rivaroxaban was not associated with significantly higher bleeding events compared to dabigatran. Intracranial bleeding, GI bleeding, stroke/SE/TIA, venous thromboembolism and mortality were also not significantly different between these two DOACs. However, due to the limited number of patients analyzed, and which were mainly obtained from observational studies, this hypothesis might only be confirmed in future randomized trials. Furthermore, the CHADS2-VASC and HAS-BLED score which might play an important role in predicting bleeding risks should also not be ignored.