Metal-Free, Hindered, Regioselective Access to Multifunctional Groups Diarylamines via SN Ar Substitution of P-Nitroso Aromatic Methyl Ether by Arylamines.

Multifunctional groups diarylamines, an innovative product, efficiently produced from arylamines and p-nitrosoanisole derivatives by intermolecular SN Ar under weak acid conditions. This SN Ar proceeds under mild reaction conditions, and more significantly, the substrates involved do not necessarily require strong electron-withdrawing groups. Moreover, this SN Ar is characterized by resistance to space crowding, tolerance to halogen and nitroso functional groups, and high regioselectivity. Mechanistic observations suggest that the SN Ar is the result of the transfer of the positive charge center of the protonated nitroso group to the p-methoxy group.

Wireless Sensing System Based on Biodegradable Triboelectric Nanogenerator for Evaluating Sports and Sleep Respiratory.

The rapid growth of the Internet of Things and wearable sensors has led to advancements in monitoring technology in the field of health. One such advancement is the development of wearable respiratory sensors, which offer a new approach to real-time respiratory monitoring compared to traditional methods. However, the energy consumption of these sensors raises concerns about environmental pollution. To address the issue, this study proposes the use of a triboelectric nanogenerator (TENG) as a sustainable energy source. The electrical conductivity of the TENG is improved by incorporating chitosan and carbon nanotubes, with the added benefit of chitosan's biodegradability reducing negative environmental impact. A wireless intelligent respiratory monitoring system (WIRMS) is then introduced, which utilizes a degradable triboelectric nanogenerator for real-time respiratory monitoring, diagnosis, and prevention of obstructive respiratory diseases. WIRMS offers stable and highly accurate respiratory information monitoring, while enabling real-time and nondestructive transmission of information. In addition, machine learning technology is used for sleep respiration state analysis. The potential applications of WIRMS extend to wearables, medical monitoring and sports monitoring, thereby presenting innovative ideas for modern medical and sports monitoring.

Recycling selectable markers via Cre/loxP system for constructing Komagataella phaffii strains co-expressing multiple proteins.

OBJECTIVE: A convenient strategy was developed to recycle selectable markers using Cre/loxP system for constructing Komagataella phaffii strains co-expressing multiple proteins. RESULTS: A plasmid in this strategy was generated from pPICZαA with integration of lox71-Sh ble-lox66. Firstly, the plasmid was inserted with one target protein gene and then transformed into K. phaffii KM71. Secondly, the auxiliary plasmid pPICZαA/cre/his4 containing CRE recombinase gene was further chromosomally inserted to Sh ble gene therein. Finally, methanol induction was conducted to produce CRE for Cre/loxP-mediated recombination, and consequently, the sequence between lox71 and lox66 was deleted, leading to recycling of ZeoR and His- markers. Then the resulted strain expressing the one target protein was used as the host to which another target protein gene could be inserted by the same procedures. CONCLUSIONS: With easy manipulation, the method was effective in recycling of the selectable markers, and consequently two protein genes were sequential integrated chromosomally and successfully co-expressed in the yeast.

Genipin protects against acute liver injury by abrogating ferroptosis via modification of GPX4 and ALOX15-launched lipid peroxidation in mice.

It is essential to further characterize liver injury aimed at developing novel therapeutic approaches. This study investigated the mechanistic basis of genipin against carbon tetrachloride (CCl4)-triggered acute liver injury concerning ferroptosis, a novel discovered modality of regulated cell death. All experiments were performed using hepatotoxic models upon CCl4 exposure in mice and human hepatocytes in vitro. Immunohistochemistry, immunoblotting, molecular docking, RNA-sequencing and ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) were conducted. CCl4 intoxication was manifested with lipid peroxidation-dictated ferroptotic cell death, together with changes in a cascade of ferroptosis-associated events and several regulatory pathways. Both the administration of genipin and ferrostatin-1 (Fer-1) significantly prevented this hepatotoxicity in response to CCl4 intoxication via upregulating GPX4 and xCT (i.e., critical regulators of ferroptosis). RNA-sequencing unraveled that arachidonic acid metabolism was considerably influenced upon genipin treatment. Accordingly, genipin treatment attenuated arachidonate 15-lipoxygenase (ALOX15)-launched lipid peroxidation in terms of UHPLC-MS/MS analysis and inflammation. In vitro, genipin supplementation rescued erastin-induced hepatocellular inviability and lipid ROS accumulation. The siRNA knockdown of GPX4 partially abrogated the protective effects of genipin on erastin-induced cytotoxicity, whereas the cytotoxicity was less severe in the presence of diminished ALOX15 expression in L-O2 cells. In conclusion, our findings uncovered that genipin treatment protects against CCl4-triggered acute liver injury by abrogating hepatocyte ferroptosis, wherein the pharmacological modification of dysregulated GPX4 and ALOX15-launched lipid peroxidation was responsible for underlying medicinal effects as molecular basis.

A novel Mcl-1 inhibitor synergizes with venetoclax to induce apoptosis in cancer cells.

BACKGROUND: Evading apoptosis by overexpression of anti-apoptotic Bcl-2 family proteins is a hallmark of cancer cells and the Bcl-2 selective inhibitor venetoclax is widely used in the treatment of hematologic malignancies. Mcl-1, another anti-apoptotic Bcl-2 family member, is recognized as the primary cause of resistance to venetoclax treatment. However, there is currently no Mcl-1 inhibitor approved for clinical use. METHODS: Paired parental and Mcl-1 knockout H1299 cells were used to screen and identify a small molecule named MI-238. Immunoprecipitation (IP) and flow cytometry assay were performed to analyze the activation of pro-apoptotic protein Bak. Annexin V staining and western blot analysis of cleaved caspase 3 were employed to measure the cell apoptosis. Mouse xenograft AML model using luciferase-expressing Molm13 cells was employed to evaluate in vivo therapeutic efficacy. Bone marrow samples from newly diagnosed AML patients were collected to evaluate the therapeutic potency. RESULTS: Here, we show that MI-238, a novel and specific Mcl-1 inhibitor, can disrupt the association of Mcl-1 with BH3-only pro-apoptotic proteins, selectively leading to apoptosis in Mcl-1 proficient cells. Moreover, MI-238 treatment also potently induces apoptosis in acute myeloid leukemia (AML) cells. Notably, the combined treatment of MI-238 with venetoclax exhibited strong synergistic anti-cancer effects in AML cells in vitro, MOLM-13 xenografts mouse model and AML patient samples. CONCLUSIONS: This study identified a novel and selective Mcl-1 inhibitor MI-238 and demonstrated that the development of MI-238 provides a novel strategy to improve the outcome of venetoclax therapy in AML.

Identifying Risk Factors for Aspiration in Patients Hospitalized with Community-Acquired Pneumonia.

Background: Aspiration pneumonia (AP) is difficult to diagnose and has poor outcomes. This case-control study aimed to explore the risk factors and delineate the antibiotic usage for AP. Methods: Inpatients diagnosed with community-acquired pneumonia (CAP) from 2013 to 2017, enrolled in the urban employee basic medical insurance program in Beijing, were included and classified into the AP (N = 2,885) and non-AP (N = 53,825) groups. Risk factors were identified by logistic regression. Results: Older age (compared to 18-64 years, OR for 65-79 years: 4.3, 95% CI: 3.8-4.9; OR for >80 years: 6.3, 95% CI: 5.6-7.2), male (OR: 1.4, 95% CI: 1.3-1.5), cerebrovascular disease (OR: 3.1, 95% CI: 2.8-3.5), dementia (OR: 2.0, 95% CI: 1.8-2.1), vomiting (OR: 1.4, 95% CI: 1.2-1.7), Parkinson's disease (OR: 2.1, 95% CI: 1.8-2.4), and epilepsy (OR: 3.2, 95% CI: 2.8-3.7) were associated with an increased risk of AP. 92.8% of the AP patients received antibiotic therapy. Among them, patients treated with broad-spectrum antibiotics, antibiotics for injection, and combined antibiotics accounted for 93.3%, 97.9%, and 81.7%, respectively. Conclusions: Older age, male, and several comorbidities were independent risk factors for AP, and combined antibiotics treatments are common, which merits attention in accurate detection of AP in a high-risk population.

Reduced muscle strength is closely linked to computed tomography-defined myosteatosis among inpatients with cirrhosis.

BACKGROUND: Myosteatosis indicates pathological fat infiltration in muscles and is regarded as a distinct disease from sarcopenia. This muscular condition exhibits a link to muscle fiber disarrangement coinciding with disrupted muscle contractility and weakened mechanical action, mirrored as decreased muscle quality. However, the relationship between handgrip strength (HGS) and computed tomography-defined myosteatosis among cirrhosis is unclear. We aimed to investigate the association between HGS and myosteatosis and determine gender-specific cutoffs regarding HGS to identify myosteatotic subjects. METHODS: We prospectively recruited 221 cirrhotic patients. The presence of myosteatosis was determined according to intramuscular adipose tissue content. The relationship between HGS and myosteatosis was evaluated according to Spearman correlation coefficient, area under the ROC curve, and multivariate logistic regression analysis. Moreover, a model based on the classification and regression tree method was generated. RESULTS: Our results showed that HGS exhibits modestly negative correlation with intramuscular adipose tissue content in the entire cohort (rs = -0.269, P < .001) and across diverse subgroups precluding extremely deteriorating conditions. After controlling for multiple clinical features and biochemical parameters, HGS (odds ratio = 0.921, P = .010) was independently associated with myosteatosis in addition to age and body mass index. On applying the Japan Society of Hepatology-recommended cutoffs, an area under the ROC curve of HGS was 0.627 with a sensitivity of 77.4% and a specificity of 47.9%. The decision tree including body mass index and low HGS correctly classified ~85% of the cases in development and validation sets. CONCLUSIONS: HGS was in close relation to myosteatosis among inpatients with cirrhosis.

The association between family function and sleep disturbances of preschool children in rural areas of China: a cross-sectional study.

This study aimed to explore the association between family function and sleep disturbances in preschool children in rural areas of China. Caregivers of preschool children completed sociodemographic questionnaires, the Children's Sleep Habits Questionnaire (CSHQ), the Self-rating Anxiety Scale (SAS) and the Family APGAR scale. Using sleep disturbances in children as the dependent variable, family function and other related factors as independent variables, binary logistic regression analyses were performed to examine associations between family function and sleep disturbances in children. A total of 3,636 caregivers of preschool children were enrolled in our study, and the prevalence of sleep disturbances among their preschool children was 89.4%. In our study, lower family function was associated with higher risk of sleep disturbances among preschool children. After adjusting for age (years), education level of mother, discipline attitudes of father and mother, only child status and caregivers' anxiety, the associations were statistically significant both in families of which caregivers of children are their parents or other relatives. (AOR for parents = 1.487, 95% CI:1.152-1.919, P = 0.002; AOR for other relatives = 1.963, 95% CI:1.302-2.958, P = 0.001). Our study results indicated that family function was associated with sleep disturbances in preschool children, and future high-quality cohort studies are needed to explore this topic in more detail.

Discovery and antitumor activity of Benzo[d]imidazol-containing 2,4-diarylaminopyrimidine analogues as ALK inhibitors with mutation-combating effects.

To address drug resistance caused by ALK kinase mutations, a series of novel 2,4-diarylaminopyrimidine (DAAP) analogues were designed by incorporating 1H-benzo[d]imidazol motif onto the maternal framework. All compounds were efficiently synthesized and antiproliferative activities against Karpas299, H2228 and A549 cell lines were evaluated by MTT assay. Delightly, the most promising derivative H-11 was detected with IC50 values of 0.016 µM and 0.099 µM against ALK- positive Karpas299 and H2228 cells. Meanwhile, H-11 displayed encouraging enzymatic inhibitory potency with IC50 values of 2.7 nM, 3.8 nM and 5.7 nM toward ALKWT, ALKL1196M and ALKG1202R, respectively. Ultimately, the binding modes of optimal H-11 with ALK wild-type and mutants were ideally established which further confirmed the structural basis in accordance with the SARs analysis.

Harmine-inspired design and synthesis of benzo[d]imidazo[2,1-b]thiazole derivatives bearing 1,3,4-oxadiazole moiety as potential tumor suppressors.

Standard chemotherapy and personalized target therapies are commonly used in patients with advanced non-small cell lung cancer (NSCLC). However, multidrug resistance (MDR) and tumor metastasis lead to the decline of therapeutic efficacy, which are closely related to epithelial-mesenchymal transition (EMT). Twist1, an EMT transcription factor, plays an essential role in promoting EMT, MDR and tumor metastasis. In view of the essential role of Twist1 in the tumorigenesis of NSCLC, developing antitumor small molecules that can suppress the expression of Twist1 is of far-reaching significance for the treatment of NSCLC. A series of novel benzo[d]imidazo[2,1-b]thiazole derivatives possessing 1,3,4-oxadiazole moiety were designed based on the structure of the first-in-class Twist1 inhibitor harmine. Among the synthetic twenty-two compounds, the compound containing 2-(piperidine-1-yl) ethyl exhibited remarkable anti-proliferative activity with IC50 value of 2.03 µM and 9.80 µM against A549 and H2228 cell lines superior to harmine (IC50 = 17.12 µM against A549, IC50 = 31.06 µM against H2228). Meanwhile, western blot assay showed that the optimal compound significantly down-regulated Twist1 protein expression in a dose-dependent manner and reduced Twist1 level better than harmine. Collectively, the promising compound was identified a potential antineoplastic lead with the ability of down-regulating Twist1 level.

Self-Powered Flexible Sour Sensor for Detecting Ascorbic Acid Concentration Based on Triboelectrification/Enzymatic-Reaction Coupling Effect.

Artificial sensory substitution systems can mimic human sensory organs through replacing the sensing process of a defective sensory receptor and transmitting the sensing signal into the nervous system. Here, we report a self-powered flexible gustation sour sensor for detecting ascorbic acid concentration. The material system comprises of Na2C2O4-Ppy with AAO modification, PDMS and Cu wire mesh. The working mechanism is contributed to the triboelectrification/enzymatic-reaction coupling effect, and the device can collect weak energy from body movements and directly output triboelectric current without any external power-units. The triboelectric output is affected by AA concentration, and the response is up to 34.82% against 15.625 mM/L of AA solution. Furthermore, a practical application in detecting ascorbic acid concentration of different drinks has been demonstrated. This work can encourage the development of wearable flexible electronics and this self-powered sour sensor has the potential that can be acted as a kind of gustatory receptors to build electronic tongues.

An Effective Self-Powered Piezoelectric Sensor for Monitoring Basketball Skills.

Self-powered piezoelectric sensor can achieve real-time and harmless monitoring of motion processes without external power supply, which can be attached on body skin or joints to detect human motion and powered by mechanical energy. Here, a sensor for monitoring emergent motion is developed using the PVDF as active material and piezoelectric output as sensing signal. The multi-point control function enables the sensor to monitor the sequence of force order, angle change, and motion frequency of the "elbow lift, arm extension, and wrist compression" during shooting basketball. In addition, the sensor shows can simultaneously charge the capacitor to provide more power for intelligence, typically Bluetooth transmission. The sensor shows good performance in other field, such as rehabilitation monitoring and speech input systems. Therefore, the emerging application of flexible sensors have huge long-term prospects in sport big data collection and Internet of Things (IoT).

The relationship between psychological resilience and emotion regulation among preschool left-behind children in rural China.

To evaluate the relationship between resilience and emotion regulation among preschool left-behind children (LBC) in rural China. A total of 620 preschool LBC were enrolled from rural areas in Anhui province, China. Multivariate logistic regression was used to evaluate the associations between resilience and variables. The results showed that 20.2% of LBC had higher resilience. Emotion regulation was correlated with resilience among preschool LBC. Children with higher cognitive reconstruction (adjusted OR (AOR) = 0.349,95%CI:0.249-0.489), passive dealing (AOR = 0.577, 95%CI:0.411-0.810), alternative action (AOR = 0.369, 95%CI:0.267-0.510) and self-comforting (AOR = 0.441, 95%CI:0.315-0.619) would have lower risk of low resilience. Our findings suggest that strengthening emotion regulation could promote psychological resilience and prevent adverse developments in LBC.

Chemical Composition and Biological Activities of Essential Oils from the Leaves, Stems, and Roots of Kadsura coccinea.

The chemical composition and biological activities of the essential oils from the leaves, stems, and roots of Kadsura coccinea (K. coccinea) were investigated. The essential oils were extracted by hydro distillation and analyzed by gas chromatography mass spectrometry (GC-MS) and gas chromatography with flame ionization detector (GC-FID). Antioxidant activities of the essential oils were examined with DPPH radical scavenging assay, ABTS cation radical scavenging assay, and ferric reducing antioxidant power assay. Antimicrobial activities were evaluated by determining minimum inhibitory concentrations (MIC) and minimum microbiocidal concentrations (MMC). Acetylcholinesterase and butyrylcholinesterase inhibitory activity of the essential oils were also tested. A total of 46, 44, and 47 components were identified in the leaf, stem, and root oils, representing 95.66%, 97.35%, and 92.72% of total composition, respectively. The major compounds of three essential oils were α-pinene (16.60-42.02%), ß-pinene (10.03-18.82%), camphene (1.56-10.95%), borneol (0.50-7.71%), δ-cadinene (1.52-7.06%), and ß-elemene (1.86-4.45%). The essential oils were found to have weak antioxidant activities and cholinesterase inhibition activities. The essential oils showed more inhibitory effects against Staphylococcus aureus (S. aureus) than those of other strains. The highest antimicrobial activity was observed in the root oil against S. aureus, with MIC of 0.78 mg/mL. Therefore, K. coccinea essential oils might be considered as a natural antibacterial agent against S. aureus with potential application in food and pharmaceutical industries.

Is periodontal disease associated with increased risk of colorectal cancer? A meta-analysis.

OBJECTIVE: Colorectal cancer (CRC) is a commonly diagnosed cancer. Previous studies investigating the relationship between periodontal disease (PD) and CRC showed controversial conclusions. This meta-analysis is to explore the association between PD and CRC. METHODS: Observational studies that explore the association between CRC and PD were included in this meta-analysis. A comprehensive literature search in 7 electronic databases to identify all relevant studies published prior to February 2020. The Newcastle-Ottawa Quality Assessment Scale was used to evaluate the quality each study. The pooled relative risk (RR) and 95% confidence interval (CI) were used to estimate the association between the PD and CRC risk. RESULTS: A total of 838 articles were obtained from database searching and 4 articles were obtained from other sources, and 13 articles with 14 studies involving 634,744 participants were included. An association between PD and increased CRC incidence was found, periodontal disease patients were 21% (95%CI, [1.06, 1.38], I2 =83.9%) more likely to develop colorectal cancer than people with healthy oral cavity. But there is no significant association between PD and CRC mortality. The heterogeneity of this meta-analysis was relatively high, I2 was 83.9% (95%CI, [72.7%, 90.5%]), chi-squared of Q test was 62.18, but sensitivity analysis confirmed the stability of the result. Funnel plot, Egger's test and Begg's test found no publication bias of analysis. CONCLUSION: The current meta-analysis demonstrates an association between PD and CRC, indicating that early CRC screening is necessary for people with poor oral health, and oral health improvement might be beneficial for reducing CRC risk.

Scoparone as a therapeutic drug in liver diseases: Pharmacology, pharmacokinetics and molecular mechanisms of action.

Scoparone is an active and efficious ingredient of herbal medicine Artemisia capillaris Thunb, which has been used clinically in traditional Chinese medicine formula (e.g. Yin-Chen-Hao decoction) for the treatment of hepatic dysfunction, cholestasis and jaundice for over thousand years. More recently, scoparone has received increasing attention due to its multiple properties. In this comprehensive review, we provide the first summary of the pharmacological effects and pharmacokinetic characteristics of scoparone, and discuss future research prospects. The results implicated that scoparone possesses a wide spectrum of pharmacological activities, including anti-inflammatory, antioxidant, anti-apoptotic, anti-fibrotic and hypolipidemic properties. Pharmacokinetic studies have addressed that isoscopoletin and scopoletin are major primary metabolites of scoparone. Moreover, hepatic dysfunction might promote bioavailability of scoparone due to limited intrinsic clearance. On the other hand, the bioavailability of multi-component including scoparone in certain TCM formula can also be enhanced by applying this formula at a high dose on account of their interacted effects. In view of good pharmacological actions, scoparone is anticipated to be a potential drug candidate for various liver diseases, such as acute liver injury, fulminant hepatitis, alcohol-induced hepatotoxicity, non-alcoholic fatty liver disease and fibrosis. However, further studies are warranted to clarify its molecular mechanisms and targets, elucidate its toxicity, and identify its interplay with other active ingredients of classical TCM formula in clinical settings.

Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: More friend than foe.

Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis. For decades, genipin is the focus of studies as a versatile compound in the treatment of various pathogenic conditions. In particularly, Gardenia jasminoides Ellis has long been used in traditional Chinese medicine for the prevention and treatment of liver disease. Mounting experimental data has proved genipin possesses therapeutic potential for cholestatic, septic, ischemia/reperfusion-triggered acute liver injury, fulminant hepatitis and NAFLD. This critical review is a reflection on the valuable lessons from decades of research regarding pharmacological activities of genipin. Of note, genipin represents choleretic effect by potentiating bilirubin disposal and enhancement of genes in charge of the efflux of a number of organic anions. The anti-inflammatory capability of genipin is mediated by suppression of the production and function of pro-inflammatory cytokines and inflammasome. Moreover, genipin modulates various transcription factor and signal transduction pathway. Genipin appears to trigger the upregulation of several key genes encoding antioxidant and xenobiotic-metabolizing enzymes. Furthermore, the medicinal impact of genipin extends to modulation of regulated cell death, including autophagic cell death, apoptosis, necroptosis and pyroptosis, and modulation of quality of cellular organelle. Another crucial effect of genipin appears to be linked to dual role in targeting uncoupling protein 2 (UCP2). As a typical UCP2-inhibiting compound, genipin could inhibit AMP-activated protein kinase or NF-κB in circumstance. On the contrary, reactive oxygen species production and cellular lipid deposits mediated by genipin through the upregulation of UCP2 is observed in liver steatosis, suggesting the precise role of genipin is disease-specific. Collectively, we comprehensively summarize the mechanisms and pathways associated with the hepatoprotective activity of genipin and discuss potential toxic impact. Notably, our focus is the direct medicinal effect of genipin itself, whereas its utility as a crosslinking agent in tissue engineering is out of scope for the current review. Further studies are therefore required to disentangle these complicated pharmacological properties to confer this natural agent a far greater potency.

Pyrroformyl-containing 2,4-diaminopyrimidine derivatives as a new optimization strategy of ALK inhibitors combating mutations.

Aiming to identify new optimization strategy effective for ALK-mutations, two series of pyrroformyl-containing 2,4-diaminopyrimidine compounds (11a-o, 12a-o) were designed, synthesized and evaluated for their anti-proliferative activities against three cancer cell lines in vitro by MTT assay. The biological evaluations on cellular assay resulted in discovery of compound 11k, which performed considerable activity with IC50 value of 0.034 µM against H2228 cell. Meanwhile, 11k exhibited outstanding enzymatic inhibitory potency with IC50 values of 1.9 nM and 3.1 nM against ALKWT and ALKL1196M, respectively, surpassing the reference ceritinib (IC50 = 2.4 nM and 7.6 nM). Ultimately, the binding mode of 11k with ALK was established to explore the SARs. Overall, 11k was considered as a promising ALK inhibitor for mutation treatment.

Fragment-based modification of 2,4-diarylaminopyrimidine derivatives as ALK and ROS1 dual inhibitors to overcome secondary mutants.

In order to explore novel ALK and ROS1 dual inhibitors capable of overcoming crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine derivatives were designed, synthesized and evaluated for their in vitro cytotoxic activity. In this work, we retained the 2,4-diarylaminopyrimidine scaffold and derivatize the DAAP scaffold with sulfonyl and acrylamide moieties to extend the structure-activity relationship (SAR) study. To our delight, some compounds exhibited excellent inhibitory activity with a double-digit nanomolar level in MTT assay. Four compounds were selected for enzymic assays further, the results led to the identification of a potent ALK and ROS1 dual inhibitor X-17, with IC50 values of 3.7 nM, 2.3 nM, 8.9 nM and 1.9 nM against ALK, ALKL1196M, ALKG1202R and ROS1, respectively. Ultimately, the molecular docking studies on X-17 clearly disclosed reasonable and optimal binding interactions with ALK.

Acid suppression therapy and its association with spontaneous bacterial peritonitis incidence: A systemic review and meta-analysis.

AIM: It is well known that the use of proton pump inhibitor (PPI) is widespread in patients with liver cirrhosis. PPI counteracts H2 receptor inhibitor (H2 RA) with its strong acid suppression effect. However, there is always a concern that PPI use may increase spontaneous bacteria peritonitis (SBP) development in cirrhotic patients. We aimed to investigate the association between acid suppression therapy (i.e. PPI or H2 RA) and SBP through meta-analysis. METHODS: We searched PubMed, Medline, Web of Science, Cochrane library, and Embase for relevant studies published up to April 2019. Pooled OR and 95% CI were calculated by a random-effects model. Funnel plots and Egger's tests were performed for the evaluation of publication bias. Non-parametric "trim-and-fill" tests were conducted for sensitivity analysis. RESULTS: A total of 20 original articles including 9566 cirrhotic patients were analyzed. The overall meta-analysis highlighted that PPI use was associated with the risk of SBP (pooled OR 1.77, 95% CI 1.49-2.11). The conclusion was irrespective of study methods, whereas the result was inconsistent only in South America. However, the conclusion might not be stable enough and should be extrapolated with caution. Unlike PPI, we found H2 RA was not associated with SBP (pooled OR 1.06, 95% CI 0.75-1.48). CONCLUSIONS: In conclusion, PPI use, but not H2 RA, will increase the incidence of SBP in cirrhotic patients. In addition, H2 RA might be beneficial for patients who require long-term acid suppression therapy.